2017

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Open AccessArticle Association of miR-938G>A Polymorphisms with Primary Ovarian Insufficiency (POI)-Related Gene Expression

by Sung Hwan Cho, Eun Hee Ahn, Hui Jeong An, Ji Hyang Kim, Jung Jae Ko, Young Ran Kim, Woo Sik Lee and Nam Keun Kim

Int. J. Mol. Sci. 2017, 18(6), 1255; doi:10.3390/ijms18061255

Received: 26 April 2017 / Revised: 28 May 2017 / Accepted: 7 June 2017 / Published: 12 June 2017

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Abstract

MicroRNAs (miRNAs) post-transcriptionally regulate gene expression in animals and plants. The aim of this study was to investigate whether polymorphisms in miR-938 are associated with the risk of primary ovarian insufficiency (POI) and POI-related target gene regulation. We identified the miR-938G>A polymorphisms

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MicroRNAs (miRNAs) post-transcriptionally regulate gene expression in animals and plants. The aim of this study was to investigate whether polymorphisms in miR-938 are associated with the risk of primary ovarian insufficiency (POI) and POI-related target gene regulation. We identified the miR-938G>A polymorphisms within the seed sequence of mature miRNA and aligned the seed sequence with the 3′ untranslated region (UTR) of the gonadotropin-releasing hormone receptor (GnRHR) mRNA, a miR-938 target gene. We found that the binding of miR-938 to the 3′-UTR of GnRHR mRNA was significantly different between normal and variant alleles. Our data suggests that the dysregulation of miR-938G>A influences the binding to GnRHR and that miR-938G>A polymorphisms might contribute to regulation of POI-related target genes. Full article

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Open AccessArticle Exome Sequencing Identified a Novel FBN2 Mutation in a Chinese Family with Congenital Contractural Arachnodactyly

by Guoling You, Bailing Zu, Bo Wang, Zhigang Wang, Yunlan Xu and Qihua Fu

Int. J. Mol. Sci. 2017, 18(4), 626; doi:10.3390/ijms18040626

Received: 6 February 2017 / Revised: 26 February 2017 / Accepted: 10 March 2017 / Published: 5 April 2017

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Abstract

Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder of connective tissue. CCA is characterized by arachnodactyly, camptodactyly, contrature of major joints, scoliosis, pectus deformities, and crumpled ears. The present study aimed to identify the genetic cause of a three-generation Chinese family with

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Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder of connective tissue. CCA is characterized by arachnodactyly, camptodactyly, contrature of major joints, scoliosis, pectus deformities, and crumpled ears. The present study aimed to identify the genetic cause of a three-generation Chinese family with CCA. We successfully identified a novel missense mutation p.G1145D in the fibrillin-2 (FBN2) gene as the pathogenic mutation by whole exome sequencing (WES). The p.G1145D mutation occurs in the 12th calcium-binding epidermal growth factor-like (cbEGF) domain. The p.G1145D mutation caused a hydrophobic to hydrophilic substitution, altering the amino acid property from neutral to acidic. Three-dimensional structural analysis showed that this mutation could alter the conformation of the residue side chain, thereby producing steric clashes with spatially adjacent residues, disrupting the formation of H bonds and causing folding destabilization. Therefore, this amino acid appears to play an important role in the structure and function of FBN2. Our results may also provide new insights into the cause and diagnosis of CCA and may have implications for genetic counseling and clinical management. Full article

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Open AccessArticle Single-Nucleotide Polymorphism of PPARγ, a Protein at the Crossroads of Physiological and Pathological Processes

by Maria Petrosino, Laura Lori, Alessandra Pasquo, Clorinda Lori, Valerio Consalvi, Velia Minicozzi, Silvia Morante, Antonio Laghezza, Alessandra Giorgi, Davide Capelli and Roberta Chiaraluce

Int. J. Mol. Sci. 2017, 18(2), 361; doi:10.3390/ijms18020361

Received: 31 October 2016 / Revised: 24 January 2017 / Accepted: 1 February 2017 / Published: 10 February 2017

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Abstract

Genome polymorphisms are responsible for phenotypic differences between humans and for individual susceptibility to genetic diseases and therapeutic responses. Non-synonymous single-nucleotide polymorphisms (nsSNPs) lead to protein variants with a change in the amino acid sequence that may affect the structure and/or function of

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Genome polymorphisms are responsible for phenotypic differences between humans and for individual susceptibility to genetic diseases and therapeutic responses. Non-synonymous single-nucleotide polymorphisms (nsSNPs) lead to protein variants with a change in the amino acid sequence that may affect the structure and/or function of the protein and may be utilized as efficient structural and functional markers of association to complex diseases. This study is focused on nsSNP variants of the ligand binding domain of PPARγ a nuclear receptor in the superfamily of ligand inducible transcription factors that play an important role in regulating lipid metabolism and in several processes ranging from cellular differentiation and development to carcinogenesis. Here we selected nine nsSNPs variants of the PPARγ ligand binding domain, V290M, R357A, R397C, F360L, P467L, Q286P, R288H, E324K, and E460K, expressed in cancer tissues and/or associated with partial lipodystrophy and insulin resistance. The effects of a single amino acid change on the thermodynamic stability of PPARγ, its spectral properties, and molecular dynamics have been investigated. The nsSNPs PPARγ variants show alteration of dynamics and tertiary contacts that impair the correct reciprocal positioning of helices 3 and 12, crucially important for PPARγ functioning. Full article

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Open AccessArticle Embryological Results of Couples Undergoing ICSI-ET Treatments with Males Carrying the Single Nucleotide Polymorphism rs175080 of the MLH3 Gene

by George Anifandis, Ourania Markandona, Konstantinos Dafopoulos, Christina Messini, Aspasia Tsezou, Marina Dimitraki, Panagiotis Georgoulias, Alexandros Daponte and Ioannis Messinis

Int. J. Mol. Sci. 2017, 18(2), 314; doi:10.3390/ijms18020314

Received: 22 October 2016 / Accepted: 26 January 2017 / Published: 2 February 2017

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Abstract

Human MLH3 (hMLH3) gene has been suggested to play a role in the DNA mismatch repair mechanism, while it may also be associated with abnormal spermatogenesis and subsequently male infertility. The aim of the present study was to investigate possible relationships between the

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Human MLH3 (hMLH3) gene has been suggested to play a role in the DNA mismatch repair mechanism, while it may also be associated with abnormal spermatogenesis and subsequently male infertility. The aim of the present study was to investigate possible relationships between the single nucleotide polymorphism (SNP) rs175080 in the MLH3 gene of males and the embryological results in couples undergoing intracytoplasmatic sperm injection-embryo transfer (ICSI-ET) treatments. A total of 132 men volunteered for the study and gave written informed consent. All couples were subjected to ICSI-ET treatments in the years 2010 to 2012. The couples were divided into three groups according to the genotype of their husbands: the wild type GG (n = 28), the heterozygotic type GA (n = 72) and the mutant type AA (n = 32). Significantly lower sperm concentration and progressive motility were observed in the AA group as compared to the other two groups (Concentration: 14.57 ± 4.9 mil/mL in AA, 38.3 ± 5.4 mil/mL in GA and 41.03 ± 6.8 mil/mL in GG, p < 0.05, mean ± standard error of the mean—SEM). However, significantly better embryological results (mean score of embryo quality–MSEQ) were found in the AA (8.12 ± 0.5) and the GA group (7.36 ± 0.4) as compared to the GG group (5.82 ± 0.7), (p < 0.05). Clinical pregnancy rate was significantly higher in the AA genotype group (43.8%) and the GA group (30.6%) than in the GG group (14.3%), (p < 0.05). Live birth rate was not different. It is suggested for the first time that the deteriorating effect of the mutant type on sperm characteristics does not impact on embryo development after fertilization in vitro. Full article

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Open AccessArticle Polymorphisms of Dopamine Receptor Genes and Risk of L-Dopa–Induced Dyskinesia in Parkinson’s Disease

by Cristoforo Comi, Marco Ferrari, Franca Marino, Luca Magistrelli, Roberto Cantello, Giulio Riboldazzi, Maria Laura Ester Bianchi, Giorgio Bono and Marco Cosentino

Int. J. Mol. Sci. 2017, 18(2), 242; doi:10.3390/ijms18020242

Received: 31 October 2016 / Revised: 11 January 2017 / Accepted: 16 January 2017 / Published: 24 January 2017

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Abstract

L-dopa–induced dyskinesia (LID) is a frequent motor complication of Parkinson’s disease (PD), associated with a negative prognosis. Previous studies showed an association between dopamine receptor (DR) gene (DR) variants and LID, the results of which have not been confirmed. The present

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L-dopa–induced dyskinesia (LID) is a frequent motor complication of Parkinson’s disease (PD), associated with a negative prognosis. Previous studies showed an association between dopamine receptor (DR) gene (DR) variants and LID, the results of which have not been confirmed. The present study is aimed to determine whether genetic differences of DR are associated with LID in a small but well-characterized cohort of PD patients. To this end we enrolled 100 PD subjects, 50 with and 50 without LID, matched for age, gender, disease duration and dopaminergic medication in a case-control study. We conducted polymerase chain reaction for single nucleotide polymorphisms (SNP) in both D1-like (DRD1A48G; DRD1C62T and DRD5T798C) and D2-like DR (DRD2G2137A, DRD2C957T, DRD3G25A, DRD3G712C, DRD4C616G and DRD4nR VNTR 48bp) analyzed genomic DNA. Our results showed that PD patients carrying allele A at DRD3G3127A had an increased risk of LID (OR 4.9; 95% CI 1.7–13.9; p = 0.004). The present findings may provide valuable information for personalizing pharmacological therapy in PD patients. Full article

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Open AccessArticle rs657075 (CSF2) Is Associated with the Disease Phenotype (BAS-G) of Ankylosing Spondylitis

by Wei-Chiao Chen, James Cheng-Chung Wei, Hsing-Fang Lu, Henry Sung-Ching Wong, Peng Yeong Woon, Yu-Wen Hsu, Jin-Ding Huang and Wei-Chiao Chang

Int. J. Mol. Sci. 2017, 18(1), 83; doi:10.3390/ijms18010083

Received: 19 September 2016 / Revised: 14 December 2016 / Accepted: 23 December 2016 / Published: 3 January 2017

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Abstract

Ankylosing spondylitis (AS) is a systemic autoimmune disease mainly affecting the lumbar spine and sacroiliac joints, and exhibits peripheral inflammatory arthropathy. More than 25 loci have been identified as associated with AS. Because both AS and rheumatoid arthritis (RA) are autoimmune diseases that

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Ankylosing spondylitis (AS) is a systemic autoimmune disease mainly affecting the lumbar spine and sacroiliac joints, and exhibits peripheral inflammatory arthropathy. More than 25 loci have been identified as associated with AS. Because both AS and rheumatoid arthritis (RA) are autoimmune diseases that may share some common genetic factors, we therefore examined if the newly identified RA genetic polymorphisms were associated with AS in a Taiwanese population. In this study, we enrolled 475 AS patients and 11,301 healthy subjects from a Taiwanese biobank as controls. Although none of single-nucleotide polymorphisms (SNPs) were associated with the susceptibility to AS, the AS disease index Bath AS Global (BAS-G) clinical phenotype was observed as significantly correlated to the AA genotype of rs657075 (CSF2). The significance remains after gender/age/disease duration adjustment and after group categorization by human leukocyte antigen-B 27 (HLA-B27) genotype. We further investigated the possible functions of rs657075 through bioinformatics approaches. Results revealed that polymorphism of rs657075 is able to influence the expression of acyl-CoA synthetase long-chain family member 6 (ACSL6). In conclusion, our study indicated that rs657075 (CSF2) is strongly associated with the AS disease index Bath AS Global (BAS-G) clinical phenotype. Full article

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2016

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Open AccessArticle Analysis to Estimate Genetic Variations in the Idarubicin-Resistant Derivative MOLT-3

by Tomoyoshi Komiyama, Atsushi Ogura, Takatsugu Hirokawa, Miao Zhijing, Hiroshi Kamiguchi, Satomi Asai, Hayato Miyachi and Hiroyuki Kobayashi

Int. J. Mol. Sci. 2017, 18(1), 12; doi:10.3390/ijms18010012

Received: 3 October 2016 / Revised: 6 December 2016 / Accepted: 13 December 2016 / Published: 22 December 2016

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Abstract

Gene alterations are a well-established mechanism leading to drug resistance in acute leukemia cells. A full understanding of the mechanisms of drug resistance in these cells will facilitate more effective chemotherapy. In this study, we investigated the mechanism(s) of drug resistance in the

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Gene alterations are a well-established mechanism leading to drug resistance in acute leukemia cells. A full understanding of the mechanisms of drug resistance in these cells will facilitate more effective chemotherapy. In this study, we investigated the mechanism(s) of drug resistance in the human acute leukemia cell line MOLT-3 and its idarubicin-resistant derivative MOLT-3/IDR through complete mitochondrial and nuclear DNA analyses. We identified genetic differences between these two cell lines. The ND3 mutation site (p.Thr61Ile) in the mitochondrial DNA sequence was unique to MOLT-3/IDR cells. Moreover, we identified five candidate genes harboring genetic alterations, including GALNT2, via CGH array analysis. Sequencing of the GALNT2 exon revealed a G1716K mutation present within the stop codon in MOLT-3/IDR cells but absent from MOLT-3 cells. This mutation led to an additional 18 amino acids in the protein encoded by GALNT2. Using real-time PCR, we determined an expression value for this gene of 0.35. Protein structure predictions confirmed a structural change in GALNT2 in MOLT-3/IDR cells that corresponded to the site of the mutation. We speculate that this mutation may be related to idarubicin resistance. Full article

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Open AccessArticle Effect of Genetic Polymorphisms and Long-Term Tobacco Exposure on the Risk of Breast Cancer

by Zoraida Verde, Catalina Santiago, Luis Miguel Chicharro, Luis Reinoso-Barbero, Alejandro Tejerina, Fernando Bandrés and Félix Gómez-Gallego

Int. J. Mol. Sci. 2016, 17(10), 1726; doi:10.3390/ijms17101726

Received: 4 July 2016 / Revised: 16 September 2016 / Accepted: 28 September 2016 / Published: 14 October 2016

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Abstract

Introduction: Tobacco smoke contains many potentially harmful compounds that may act differently and at different stages in breast cancer development. The focus of this work was to assess the possible role of cigarette smoking (status, dose, duration or age at initiation) and polymorphisms

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Introduction: Tobacco smoke contains many potentially harmful compounds that may act differently and at different stages in breast cancer development. The focus of this work was to assess the possible role of cigarette smoking (status, dose, duration or age at initiation) and polymorphisms in genes coding for enzymes involved in tobacco carcinogen metabolism (CYP1A1, CYP2A6) or in DNA repair (XRCC1, APEX1, XRCC3 and XPD) in breast cancer development. Methods: We designed a case control study with 297 patients, 217 histologically verified breast cancers (141 smokers and 76 non-smokers) and 80 healthy smokers in a cohort of Spanish women. Results: We found an association between smoking status and early age at diagnosis of breast cancer. Among smokers, invasive carcinoma subtype incidence increased with intensity and duration of smoking (all P_trend < 0.05). When smokers were stratified by smoking duration, we only observed differences in long-term smokers, and the CYP1A1 Ile462Ile genotype was associated with increased risk of breast cancer (OR = 7.12 (1.98–25.59)). Conclusions: Our results support the main effect of CYP1A1 in estrogenic metabolism rather than in tobacco carcinogen activation in breast cancer patients and also confirmed the hypothesis that CYP1A1 Ile462Val, in association with long periods of active smoking, could be a breast cancer risk factor. Full article

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Open AccessArticle A Genomics-Based Model for Prediction of Severe Bioprosthetic Mitral Valve Calcification

by Anastasia V. Ponasenko, Maria V. Khutornaya, Anton G. Kutikhin, Natalia V. Rutkovskaya, Anna V. Tsepokina, Natalia V. Kondyukova, Arseniy E. Yuzhalin and Leonid S. Barbarash

Int. J. Mol. Sci. 2016, 17(9), 1385; doi:10.3390/ijms17091385

Received: 23 June 2016 / Revised: 9 August 2016 / Accepted: 19 August 2016 / Published: 31 August 2016

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Abstract

Severe bioprosthetic mitral valve calcification is a significant problem in cardiovascular surgery. Unfortunately, clinical markers did not demonstrate efficacy in prediction of severe bioprosthetic mitral valve calcification. Here, we examined whether a genomics-based approach is efficient in predicting the risk of severe bioprosthetic

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Severe bioprosthetic mitral valve calcification is a significant problem in cardiovascular surgery. Unfortunately, clinical markers did not demonstrate efficacy in prediction of severe bioprosthetic mitral valve calcification. Here, we examined whether a genomics-based approach is efficient in predicting the risk of severe bioprosthetic mitral valve calcification. A total of 124 consecutive Russian patients who underwent mitral valve replacement surgery were recruited. We investigated the associations of the inherited variation in innate immunity, lipid metabolism and calcium metabolism genes with severe bioprosthetic mitral valve calcification. Genotyping was conducted utilizing the TaqMan assay. Eight gene polymorphisms were significantly associated with severe bioprosthetic mitral valve calcification and were therefore included into stepwise logistic regression which identified male gender, the T/T genotype of the rs3775073 polymorphism within the TLR6 gene, the C/T genotype of the rs2229238 polymorphism within the IL6R gene, and the A/A genotype of the rs10455872 polymorphism within the LPA gene as independent predictors of severe bioprosthetic mitral valve calcification. The developed genomics-based model had fair predictive value with area under the receiver operating characteristic (ROC) curve of 0.73. In conclusion, our genomics-based approach is efficient for the prediction of severe bioprosthetic mitral valve calcification. Full article

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Open AccessArticle Chromosome 9p21 and ABCA1 Genetic Variants and Their Interactions on Coronary Heart Disease and Ischemic Stroke in a Chinese Han Population

by Xiao-Li Cao, Rui-Xing Yin, Feng Huang, Jin-Zhen Wu and Wu-Xian Chen

Int. J. Mol. Sci. 2016, 17(4), 586; doi:10.3390/ijms17040586

Received: 12 March 2016 / Revised: 6 April 2016 / Accepted: 14 April 2016 / Published: 18 April 2016

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Abstract

The single nucleotide polymorphisms (SNPs) related to both coronary heart disease (CHD) and ischemic stroke (IS) in Chinese individuals have not been identified definitely. This study was developed to evaluate the genetic susceptibility to CHD and IS on the chromosome 9p21 and the

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The single nucleotide polymorphisms (SNPs) related to both coronary heart disease (CHD) and ischemic stroke (IS) in Chinese individuals have not been identified definitely. This study was developed to evaluate the genetic susceptibility to CHD and IS on the chromosome 9p21 and the adenosine triphosphate (ATP)-binding cassette transporter A1 genes (ABCA1) in a Chinese Han population. Genotypes of the rs1333040, rs1333042, rs4977574, rs2066715 and rs2740483 SNPs were determined in 1134 unrelated patients (CHD, 565 and IS, 569) and 541 controls. The frequencies of the rs4977574 genotypes and alleles between CHD and control groups, and the rs2740483 genotypes and alleles between IS and control groups were different (p = 0.006–0.001). The subjects with rs1333042GG genotype and the carriers of the rs4977574G allele were associated with increased risk of CHD. The carriers of the rs4977574G allele were associated with increased risk of IS. However, the carriers of the rs2740483C allele had lower risk of IS than the non-carriers of the rs2740483C allele after controlling for potential confounders. The rs4977574GG-age (>60 year) interaction increased the risk of CHD (p = 0.022), whereas the rs2740483CG/CC-body mass index (>24 kg/m²) interaction decreased the risk of IS (p = 0.035). The interactions of rs1333040-rs1333042 on the risk of CHD and IS were relatively strong, whereas the interactions of rs1333040-rs1333042-rs2066715 and rs1333040-rs1333042-rs2066715-rs2740483 on the risk of CHD, and rs1333040-rs1333042-rs4977574 and rs1333040-rs1333042-rs4977574-rs2740483 on the risk of IS were relatively weak. These findings suggest that some common variants on the chromosome 9p21 and ABCA1 and their interactions may significantly modify the risk of CHD and IS independent of effects on serum lipid levels. Full article

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Open AccessArticle SAAMBE: Webserver to Predict the Charge of Binding Free Energy Caused by Amino Acids Mutations

by Marharyta Petukh, Luogeng Dai and Emil Alexov

Int. J. Mol. Sci. 2016, 17(4), 547; doi:10.3390/ijms17040547

Received: 12 February 2016 / Revised: 5 April 2016 / Accepted: 7 April 2016 / Published: 12 April 2016

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Abstract

Predicting the effect of amino acid substitutions on protein–protein affinity (typically evaluated via the change of protein binding free energy) is important for both understanding the disease-causing mechanism of missense mutations and guiding protein engineering. In addition, researchers are also interested in understanding

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Predicting the effect of amino acid substitutions on protein–protein affinity (typically evaluated via the change of protein binding free energy) is important for both understanding the disease-causing mechanism of missense mutations and guiding protein engineering. In addition, researchers are also interested in understanding which energy components are mostly affected by the mutation and how the mutation affects the overall structure of the corresponding protein. Here we report a webserver, the Single Amino Acid Mutation based change in Binding free Energy (SAAMBE) webserver, which addresses the demand for tools for predicting the change of protein binding free energy. SAAMBE is an easy to use webserver, which only requires that a coordinate file be inputted and the user is provided with various, but easy to navigate, options. The user specifies the mutation position, wild type residue and type of mutation to be made. The server predicts the binding free energy change, the changes of the corresponding energy components and provides the energy minimized 3D structure of the wild type and mutant proteins for download. The SAAMBE protocol performance was tested by benchmarking the predictions against over 1300 experimentally determined changes of binding free energy and a Pearson correlation coefficient of 0.62 was obtained. How the predictions can be used for discriminating disease-causing from harmless mutations is discussed. The webserver can be accessed via http://compbio.clemson.edu/saambe_webserver/. Full article

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Open AccessArticle SAAFEC: Predicting the Effect of Single Point Mutations on Protein Folding Free Energy Using a Knowledge-Modified MM/PBSA Approach

by Ivan Getov, Marharyta Petukh and Emil Alexov

Int. J. Mol. Sci. 2016, 17(4), 512; doi:10.3390/ijms17040512

Received: 7 January 2016 / Accepted: 28 March 2016 / Published: 7 April 2016

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Abstract

Folding free energy is an important biophysical characteristic of proteins that reflects the overall stability of the 3D structure of macromolecules. Changes in the amino acid sequence, naturally occurring or made in vitro, may affect the stability of the corresponding protein and

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Folding free energy is an important biophysical characteristic of proteins that reflects the overall stability of the 3D structure of macromolecules. Changes in the amino acid sequence, naturally occurring or made in vitro, may affect the stability of the corresponding protein and thus could be associated with disease. Several approaches that predict the changes of the folding free energy caused by mutations have been proposed, but there is no method that is clearly superior to the others. The optimal goal is not only to accurately predict the folding free energy changes, but also to characterize the structural changes induced by mutations and the physical nature of the predicted folding free energy changes. Here we report a new method to predict the Single Amino Acid Folding free Energy Changes (SAAFEC) based on a knowledge-modified Molecular Mechanics Poisson-Boltzmann (MM/PBSA) approach. The method is comprised of two main components: a MM/PBSA component and a set of knowledge based terms delivered from a statistical study of the biophysical characteristics of proteins. The predictor utilizes a multiple linear regression model with weighted coefficients of various terms optimized against a set of experimental data. The aforementioned approach yields a correlation coefficient of 0.65 when benchmarked against 983 cases from 42 proteins in the ProTherm database. Availability: the webserver can be accessed via http://compbio.clemson.edu/SAAFEC/. Full article

Open AccessArticle RORC2 Genetic Variants and Serum Levels in Patients with Rheumatoid Arthritis

by Agnieszka Paradowska-Gorycka, Barbara Stypinska, Andrzej Pawlik, Katarzyna Romanowska-Prochnicka, Ewa Haladyj, Malgorzata Manczak and Marzena Olesinska

Int. J. Mol. Sci. 2016, 17(4), 488; doi:10.3390/ijms17040488

Received: 15 February 2016 / Revised: 17 March 2016 / Accepted: 21 March 2016 / Published: 1 April 2016

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Abstract

Background: In the present study, we aimed to evaluate whether polymorphisms within the RORc2 gene are involved in the risk and severity of rheumatoid arthritis (RA). Methods: 591 RA patients and 341 healthy individuals were examined for RORc2 gene polymorphisms. Serum retinoic acid

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Background: In the present study, we aimed to evaluate whether polymorphisms within the RORc2 gene are involved in the risk and severity of rheumatoid arthritis (RA). Methods: 591 RA patients and 341 healthy individuals were examined for RORc2 gene polymorphisms. Serum retinoic acid receptor-related orphan receptor C (RORc) levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: The rs9826 A/G, rs12045886 T/C and rs9017 G/A RORc2 gene SNPs show no significant differences in the proportion of cases and control. Overall, rs9826 and rs9017 were in high linkage disequilibrium (LD) with D’ = 0.952 and r² = 0.874, except rs9826 and rs12045886; and rs12045886 and rs9017 in weak LD. The genotype–phenotype analysis showed a significant association between RORc2 rs9826 A/G and rs9017 G/A single nucleotide polymorphisms (SNPs) and median of C-reactive protein (CRP). Serum RORc levels was higher in RA patients with rs9826AA, rs12045886TT and -TC, and rs9017AA genotypes compared to healthy subjects with the same genotypes (p = 0.02, p = 0.04 and p = 0.01, respectively). Moreover, the median of RORc protein level was higher in RA patients with number of swollen joints bigger then 3 (p = 0.04) and with Health Assessment Questionnaires (HAQ) score bigger then 1.5 (0.049). Conclusions: Current findings indicated that the RORc2 genetic polymorphism and the RORc2 protein level may be associated with severity of RA in the Polish population. Full article

Open AccessArticle Intronic Polymorphisms in the CDKN2B-AS1 Gene Are Strongly Associated with the Risk of Myocardial Infarction and Coronary Artery Disease in the Saudi Population

by Sayed AbdulAzeez, Awatif N. Al-Nafie, Abdullah Al-Shehri, J. Francis Borgio, Ekaterina V. Baranova, Mohammed S. Al-Madan, Rudaynah A. Al-Ali, Fahad Al-Muhanna, Abdullah Al-Ali, Mohammed Al-Mansori, Mohammed Fakhry Ibrahim, Folkert W. Asselbergs, Brendan Keating, Bobby P. C. Koeleman and Amein K. Al-Ali

Int. J. Mol. Sci. 2016, 17(3), 395; doi:10.3390/ijms17030395

Received: 8 February 2016 / Revised: 2 March 2016 / Accepted: 11 March 2016 / Published: 17 March 2016

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Abstract

Recent genome-wide association studies identified single nucleotide polymorphisms (SNPs) on the chromosome 9p21.3 conferring the risk for CAD (coronary artery disease) in individuals of Caucasian ancestry. We performed a genetic association study to investigate the effect of 12 candidate SNPs within 9p21.3 locus

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Recent genome-wide association studies identified single nucleotide polymorphisms (SNPs) on the chromosome 9p21.3 conferring the risk for CAD (coronary artery disease) in individuals of Caucasian ancestry. We performed a genetic association study to investigate the effect of 12 candidate SNPs within 9p21.3 locus on the risk of CAD in the Saudi population of the Eastern Province of Saudi Arabia. A total of 250 Saudi CAD patients who had experienced an myocardial infarction (MI) and 252 Saudi age-matched healthy controls were genotyped using TaqMan assay. Controls with evidenced lack of CAD provided 90% of statistical power at the type I error rate of 0.05. Five percent of the results were rechecked for quality control using Sanger sequencing, the results of which concurred with the TaqMan genotyping results. Association analysis of 12 SNPs indicated a significant difference in the genotype distribution for four SNPs between cases and controls (rs564398 p = 0.0315, χ² = 4.6, odds ratio (OD) = 1.5; rs4977574 p = 0.0336, χ² = 4.5, OD = 1.4; rs2891168 p = 1.85 × 10 − 10, χ² = 40.6, OD = 2.1 and rs1333042 p = 5.14 × 10 − 9, χ² = 34.1, OD = 2.2). The study identified three protective haplotypes (TAAG p = 1.00 × 10 − 4; AGTA p = 0.022 and GGGCC p = 0.0175) and a risk haplotype (TGGA p = 2.86 × 10 − 10) for the development of CAD. This study is in line with others that indicated that the SNPs located in the intronic region of the CDKN2B-AS1 gene are associated with CAD. Full article

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Open AccessArticle Sanger Sequencing for BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del Mutation Screen on Pap Smear Cytology Samples

by Sin Hang Lee, Shaoxia Zhou, Tianjun Zhou and Guofan Hong

Int. J. Mol. Sci. 2016, 17(2), 229; doi:10.3390/ijms17020229

Received: 6 December 2015 / Revised: 1 February 2016 / Accepted: 4 February 2016 / Published: 8 February 2016

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Abstract

Three sets of polymerase chain reaction (PCR) primers were designed for heminested PCR amplification of the target DNA fragments in the human genome which include the site of BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del respectively, to prepare the templates for direct Sanger

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Three sets of polymerase chain reaction (PCR) primers were designed for heminested PCR amplification of the target DNA fragments in the human genome which include the site of BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del respectively, to prepare the templates for direct Sanger sequencing screen of these three founder mutations. With a robust PCR mixture, crude proteinase K digestate of the fixed cervicovaginal cells in the liquid-based Papanicolaou (Pap) cytology specimens can be used as the sample for target DNA amplification without pre-PCR DNA extraction, purification and quantitation. The post-PCR products can be used directly as the sequencing templates without further purification or quantitation. By simplifying the frontend procedures for template preparation, the cost for screening these three founder mutations can be reduced to about US $200 per test when performed in conjunction with human papillomavirus (HPV) assays now routinely ordered for cervical cancer prevention. With this projected price structure, selective patients in a high-risk population can be tested and each provided with a set of DNA sequencing electropherograms to document the absence or presence of these founder mutations in her genome to help assess inherited susceptibility to breast and ovarian cancer in this era of precision molecular personalized medicine. Full article

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Open AccessArticle Revealing the Effects of Missense Mutations Causing Snyder-Robinson Syndrome on the Stability and Dimerization of Spermine Synthase

by Yunhui Peng, Joy Norris, Charles Schwartz and Emil Alexov

Int. J. Mol. Sci. 2016, 17(1), 77; doi:10.3390/ijms17010077

Received: 14 November 2015 / Revised: 28 December 2015 / Accepted: 4 January 2016 / Published: 8 January 2016

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Abstract

Missense mutations in spermine synthase (SpmSyn) protein have been shown to cause the Snyder-Robinson syndrome (SRS). Depending on the location within the structure of SpmSyn and type of amino acid substitution, different mechanisms resulting in SRS were proposed. Here we focus on naturally

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Missense mutations in spermine synthase (SpmSyn) protein have been shown to cause the Snyder-Robinson syndrome (SRS). Depending on the location within the structure of SpmSyn and type of amino acid substitution, different mechanisms resulting in SRS were proposed. Here we focus on naturally occurring amino acid substitutions causing SRS, which are situated away from the active center of SpmSyn and thus are not directly involved in the catalysis. Two of the mutations, M35R and P112L, are reported for the first time in this study. It is demonstrated, both experimentally and computationally, that for such mutations the major effect resulting in dysfunctional SpmSyn is the destabilization of the protein. In vitro experiments indicated either no presence or very little amount of the mutant SpmSyn in patient cells. In silico modeling predicted that all studied mutations in this work destabilize SpmSyn and some of them abolish homo-dimer formation. Since dimerization and structural stability are equally important for the wild type function of SpmSyn, it is proposed that the SRS caused by mutations occurring in the N-domain of SpmSyn is a result of dysfunctional mutant proteins being partially unfolded and degraded by the proteomic machinery of the cell or being unable to form a homo-dimer. Full article

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2015

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Open AccessArticle Association of the rs1346044 Polymorphism of the Werner Syndrome Gene RECQL2 with Increased Risk and Premature Onset of Breast Cancer

by Karin Zins, Barbara Frech, Eva Taubenschuss, Christian Schneeberger, Dietmar Abraham and Martin Schreiber

Int. J. Mol. Sci. 2015, 16(12), 29643-29653; doi:10.3390/ijms161226192

Received: 23 October 2015 / Revised: 27 November 2015 / Accepted: 3 December 2015 / Published: 10 December 2015

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Abstract

Like other RECQ helicases, WRN/RECQL2 plays a crucial role in DNA replication and the maintenance of genome stability. Inactivating mutations in RECQL2 lead to Werner syndrome, a rare autosomal disease associated with premature aging and an increased susceptibility to multiple cancer types. We

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Like other RECQ helicases, WRN/RECQL2 plays a crucial role in DNA replication and the maintenance of genome stability. Inactivating mutations in RECQL2 lead to Werner syndrome, a rare autosomal disease associated with premature aging and an increased susceptibility to multiple cancer types. We analyzed the association of two coding single-nucleotide polymorphisms in WRN, Cys1367Arg (rs1346044), and Arg834Cys (rs3087425), with the risk, age at onset, and clinical subclasses of breast cancer in a hospital-based case-control study of an Austrian population of 272 breast cancer patients and 254 controls. Here we report that the rare homozygous CC genotype of rs1346044 was associated with an approximately two-fold elevated breast cancer risk. Moreover, patients with the CC genotype exhibited a significantly increased risk of developing breast cancer under the age of 55 in both recessive and log-additive genetic models. CC patients developed breast cancer at a mean age of 55.2 ± 13.3 years and TT patients at 60.2 ± 14.7 years. Consistently, the risk of breast cancer was increased in pre-menopausal patients in the recessive model. These findings suggest that the CC genotype of WRN rs1346044 may contribute to an increased risk and a premature onset of breast cancer. Full article

Open AccessReview An Updated Review on the Genetics of Primary Open Angle Glaucoma

by Khaled Abu-Amero, Altaf A. Kondkar and Kakarla V. Chalam

Int. J. Mol. Sci. 2015, 16(12), 28886-28911; doi:10.3390/ijms161226135

Received: 27 October 2015 / Revised: 19 November 2015 / Accepted: 27 November 2015 / Published: 4 December 2015

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Abstract

Epidemiological studies suggest that by 2020 the prevalence of primary open angle glaucoma (POAG) is estimated to increase to 76.0 million, and to 111.8 million by 2040 globally due to the population aging. The prevalence of POAG is the highest among those of

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Epidemiological studies suggest that by 2020 the prevalence of primary open angle glaucoma (POAG) is estimated to increase to 76.0 million, and to 111.8 million by 2040 globally due to the population aging. The prevalence of POAG is the highest among those of African descent, followed by Asians, and the lowest in Europeans. POAG is a genetically complex trait with a substantial fraction exhibiting a significant heritability. Less than 10% of POAG cases in the general population are caused by specific gene mutations and the remaining cases are polygenic. Quantitative traits related to POAG pathogenesis such as intra-ocular pressure (IOP), vertical cup/disc ratio (VCDR), optic disc area, and central corneal thickness (CCT) are highly heritable, and likely to be influenced at least in part by genes and show substantial variation in human populations. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) at different loci including CAV1/CAV2, TMCO1, CDKN2B-AS1, CDC7-TGFBR3, SIX1/SIX6, GAS7 and ATOH7 to be associated with POAG and its related quantitative traits (endophenotypes). The chapter provides a brief overview on the different GWAS and SNP association studies and their correlation with various clinical parameters important for POAG in the population worldwide, including the Middle East. Full article

Open AccessArticle A Multiple Interaction Analysis Reveals ADRB3 as a Potential Candidate for Gallbladder Cancer Predisposition via a Complex Interaction with Other Candidate Gene Variations

by Rajani Rai, Jong Joo Kim, Sanjeev Misra, Ashok Kumar and Balraj Mittal

Int. J. Mol. Sci. 2015, 16(12), 28038-28049; doi:10.3390/ijms161226077

Received: 16 October 2015 / Revised: 12 November 2015 / Accepted: 13 November 2015 / Published: 25 November 2015

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Abstract

Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors.

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Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors. Previously, we demonstrated the association of several candidate gene variations with GBC risk. In this study, we aimed to identify the combination of gene variants and their possible interactions contributing towards genetic susceptibility of GBC. Here, we performed Multifactor-Dimensionality Reduction (MDR) and Classification and Regression Tree Analysis (CRT) to investigate the gene–gene interactions and the combined effect of 14 SNPs in nine genes (DR4 (rs20576, rs6557634); FAS (rs2234767); FASL (rs763110); DCC (rs2229080, rs4078288, rs7504990, rs714); PSCA (rs2294008, rs2978974); ADRA2A (rs1801253); ADRB1 (rs1800544); ADRB3 (rs4994); CYP17 (rs2486758)) involved in various signaling pathways. Genotyping was accomplished by PCR-RFLP or Taqman allelic discrimination assays. SPSS software version 16.0 and MDR software version 2.0 were used for all the statistical analysis. Single locus investigation demonstrated significant association of DR4 (rs20576, rs6557634), DCC (rs714, rs2229080, rs4078288) and ADRB3 (rs4994) polymorphisms with GBC risk. MDR analysis revealed ADRB3 (rs4994) to be crucial candidate in GBC susceptibility that may act either alone (p < 0.0001, CVC = 10/10) or in combination with DCC (rs714 and rs2229080, p < 0.0001, CVC = 9/10). Our CRT results are in agreement with the above findings. Further, in-silico results of studied SNPs advocated their role in splicing, transcriptional and/or protein coding regulation. Overall, our result suggested complex interactions amongst the studied SNPs and ADRB3 rs4994 as candidate influencing GBC susceptibility. Full article

Open AccessArticle Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease

by Yunhui Peng, Jimmy Suryadi, Ye Yang, Tugba G. Kucukkal, Weiguo Cao and Emil Alexov

Int. J. Mol. Sci. 2015, 16(11), 27270-27287; doi:10.3390/ijms161126022

Received: 31 August 2015 / Revised: 1 November 2015 / Accepted: 4 November 2015 / Published: 13 November 2015

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Abstract

Mutations in KDM5C gene are linked to X-linked mental retardation, the syndromic Claes-Jensen-type disease. This study focuses on non-synonymous mutations in the KDM5C ARID domain and evaluates the effects of two disease-associated missense mutations (A77T and D87G) and three not-yet-classified missense mutations (R108W,

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Mutations in KDM5C gene are linked to X-linked mental retardation, the syndromic Claes-Jensen-type disease. This study focuses on non-synonymous mutations in the KDM5C ARID domain and evaluates the effects of two disease-associated missense mutations (A77T and D87G) and three not-yet-classified missense mutations (R108W, N142S, and R179H). We predict the ARID domain’s folding and binding free energy changes due to mutations, and also study the effects of mutations on protein dynamics. Our computational results indicate that A77T and D87G mutants have minimal effect on the KDM5C ARID domain stability and DNA binding. In parallel, the change in the free energy unfolding caused by the mutants A77T and D87G were experimentally measured by urea-induced unfolding experiments and were shown to be similar to the in silico predictions. The evolutionary conservation analysis shows that the disease-associated mutations are located in a highly-conserved part of the ARID structure (N-terminal domain), indicating their importance for the KDM5C function. N-terminal residues’ high conservation suggests that either the ARID domain utilizes the N-terminal to interact with other KDM5C domains or the N-terminal is involved in some yet unknown function. The analysis indicates that, among the non-classified mutations, R108W is possibly a disease-associated mutation, while N142S and R179H are probably harmless. Full article

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Open AccessArticle Rare Titin (TTN) Variants in Diseases Associated with Sudden Cardiac Death

by Oscar Campuzano, Olallo Sanchez-Molero, Irene Mademont-Soler, Helena Riuró, Catarina Allegue, Monica Coll, Alexandra Pérez-Serra, Jesus Mates, Ferran Picó, Anna Iglesias and Ramon Brugada

Int. J. Mol. Sci. 2015, 16(10), 25773-25787; doi:10.3390/ijms161025773

Received: 22 July 2015 / Revised: 12 October 2015 / Accepted: 19 October 2015 / Published: 27 October 2015

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Abstract

A leading cause of death in western countries is sudden cardiac death, and can be associated with genetic disease. Next-generation sequencing has allowed thorough analysis of genes associated with this entity, including, most recently, titin. We aimed to identify potentially pathogenic genetic variants

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A leading cause of death in western countries is sudden cardiac death, and can be associated with genetic disease. Next-generation sequencing has allowed thorough analysis of genes associated with this entity, including, most recently, titin. We aimed to identify potentially pathogenic genetic variants in titin. A total of 1126 samples were analyzed using a custom sequencing panel including major genes related to sudden cardiac death. Our cohort was divided into three groups: 432 cases from patients with cardiomyopathies, 130 cases from patients with channelopathies, and 564 post-mortem samples from individuals showing anatomical healthy hearts and non-conclusive causes of death after comprehensive autopsy. None of the patients included had definite pathogenic variants in the genes analyzed by our custom cardio-panel. Retrospective analysis comparing the in-house database and available public databases also was performed. We identified 554 rare variants in titin, 282 of which were novel. Seven were previously reported as pathogenic. Of these 554 variants, 493 were missense variants, 233 of which were novel. Of all variants identified, 399 were unique and 155 were identified at least twice. No definite pathogenic variants were identified in any of genes analyzed. We identified rare, mostly novel, titin variants that seem to play a potentially pathogenic role in sudden cardiac death. Additional studies should be performed to clarify the role of these variants in sudden cardiac death. Full article

Open AccessArticle Association of the C-Reactive Protein Gene (CRP) rs1205 C>T Polymorphism with Aortic Valve Calcification in Patients with Aortic Stenosis

by Ewa Wypasek, Daniel P. Potaczek and Anetta Undas

Int. J. Mol. Sci. 2015, 16(10), 23745-23759; doi:10.3390/ijms161023745

Received: 1 July 2015 / Revised: 28 August 2015 / Accepted: 31 August 2015 / Published: 9 October 2015

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Abstract

Elevation in C-reactive protein (CRP) levels have been shown in patients with aortic valve stenosis (AS). Minor allele of the CRP gene (CRP) rs1205 C>T polymorphism has been associated with lower plasma CRP concentrations in cohorts of healthy and atherosclerotic patients.

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Elevation in C-reactive protein (CRP) levels have been shown in patients with aortic valve stenosis (AS). Minor allele of the CRP gene (CRP) rs1205 C>T polymorphism has been associated with lower plasma CRP concentrations in cohorts of healthy and atherosclerotic patients. Considering the existing similarities between atherosclerosis and AS, we examined the effect of CRP rs1205 C>T polymorphism on the AS severity. Three hundred consecutive Caucasian patients diagnosed with AS were genotyped for the rs1205 C>T polymorphism using the TaqMan assay. Severity of the AS was assessed using transthoracic echocardiography. The degree of calcification was analyzed semi-quantitatively. Carriers of the rs1205 T allele were characterized by elevated serum CRP levels (2.53 (1.51–3.96) vs. 1.68 (0.98–2.90) mg/L, p < 0.001) and a higher proportion of the severe aortic valve calcification (70.4% vs. 55.1%, p = 0.01) compared with major homozygotes. The effect of CRP rs1205 polymorphism on CRP levels is opposite in AS-affected than in unaffected subjects, suggesting existence of a disease-specific molecular regulatory mechanism. Furthermore, rs1205 variant allele predisposes to larger aortic valve calcification, potentially being a novel genetic risk marker of disease progression. Full article

Open AccessArticle Association of Nicotinamide Phosphoribosyltransferase (NAMPT) Gene Polymorphisms and of Serum NAMPT Levels with Dilated Cardiomyopathy in a Chinese Population

by Qingyu Dou, Ying Peng, Bin Zhou, Kui Zhang, Jing Lin, Xiaohui Dai, Lin Zhang and Li Rao

Int. J. Mol. Sci. 2015, 16(9), 22299-22318; doi:10.3390/ijms160922299

Received: 21 June 2015 / Revised: 2 September 2015 / Accepted: 6 September 2015 / Published: 15 September 2015

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Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) has crucial roles for myocardial development, cardiomyocyte energy metabolism and cell death/survival by regulating NAD⁺-dependent sirtuin-1 (SIRT1) deacetylase. This study aimed to determine if the single nucleotide polymorphisms (SNPs) of the NAMPT gene may affect the susceptibility and

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Nicotinamide phosphoribosyltransferase (NAMPT) has crucial roles for myocardial development, cardiomyocyte energy metabolism and cell death/survival by regulating NAD⁺-dependent sirtuin-1 (SIRT1) deacetylase. This study aimed to determine if the single nucleotide polymorphisms (SNPs) of the NAMPT gene may affect the susceptibility and prognosis for patients with dilated cardiomyopathy (DCM) and to describe the association of serum NAMPT levels with clinical features of DCM. Three SNPs (rs61330082, rs2505568, and rs9034) were analyzed by the polymerase chain reaction-restriction fragment length polymorphism method in a case-control study of 394 DCM patients and 395 controls from China. Serum NAMPT levels were measured by enzyme-linked immunosorbent assay kits. The homozygote for the minor allele at rs2505568 and rs9034 could not be detected in this study. Rs9034 T allele and CT genotype were associated with increased DCM risk (OR: 1.63, 95% CI = 1.16–2.27, p = 0.005 and OR: 1.72, 95% CI = 1.20–2.50, p = 0.0027, respectively). Nominally significant decreased DCM risk was found to be associated with the A allele and AT genotype of rs2505568 (OR: 0.48, 95% CI = 0.35–0.67, p < 0.0001 and OR: 0.44, 95% CI = 0.31–0.62, p < 0.0001, respectively), but it should be interpreted with caution because of Hardy-Weinberg disequilibrium in the control group. Of five haplotypes constructed, TAC (rs61330082-rs2505568-rs9034) was a protective haplotype to DCM (OR: 0.22, 95% CI = 0.13–0.39, p = 1.84 × 10⁻⁸). The Cox multivariate survival analysis indicated that the rs9034 CT genotype (hazard ratio (HR): 0.59, 95% CI = 0.37–0.96, p = 0.03) was an independently multivariate predictor for longer overall survival in DCM patients. Serum NAMPT levels were significantly higher in the DCM group than controls (p < 0.0001) and gradually increased with the increase of New York Heart Association grade in DCM patients. However, there was a lack of association of the three SNPs with serum NAMPT levels. Spearman correlation test revealed that the NAMPT level was positively associated with brain natriuretic peptide (r = 0.56, p = 0.001), left ventricular end-diastolic diameter (r = 0.293, p = 0.011) and left ventricular end-diastolic volume (r = 0.294, p = 0.011). Our study suggested that NAMPT may play an important role in the development of DCM. Full article

Open AccessArticle Duplex High-Resolution Melting Assay for the Simultaneous Genotyping of IL28B rs12979860 and PNPLA3 rs738409 Polymorphisms in Chronic Hepatitis C Patients

by Elena L. Enache, Anca Sin, Ligia Bancu, Christophe Ramière, Olivier Diaz, Patrice André and Liviu S. Enache

Int. J. Mol. Sci. 2015, 16(9), 22223-22242; doi:10.3390/ijms160922223

Received: 10 July 2015 / Revised: 2 September 2015 / Accepted: 8 September 2015 / Published: 14 September 2015

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Abstract

Chronic hepatitis C (CHC) is a major burden for public health worldwide. Although newer direct-acting antivirals show good efficacy, their cost precludes their wide adoption in resource-limited regions. Thus, strategies are being developed to help identify patients with high susceptibility to response to

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Chronic hepatitis C (CHC) is a major burden for public health worldwide. Although newer direct-acting antivirals show good efficacy, their cost precludes their wide adoption in resource-limited regions. Thus, strategies are being developed to help identify patients with high susceptibility to response to classic PEG-interferon + ribavirin therapy. IL28B polymorphism rs12979860 C/T is an important predictor for an efficient response to interferon-based therapy. A genetic variant in adiponutrin (PNPLA3) gene, rs738409 C/G, is associated with steatosis, severity, and progression of liver fibrosis in CHC patients, and predicts treatment outcome in difficult-to-cure HCV-infected patients with advanced fibrosis. We developed a rapid and inexpensive assay based on duplex high-resolution melting (HRM) for the simultaneous genotyping of these two polymorphisms. The assay validation was performed on synthetic DNA templates and 132 clinical samples from CHC patients. When compared with allele-specific PCR and sequencing, our assay showed 100% (95% CI: 0.9724–1) accuracy, with 100% sensitivity and specificity. Our assay was robust against concentration and quality of DNA samples, melting curve normalization intervals, HRM analysis algorithm, and sequence variations near the targeted SNPs (single nucleotide polymorphism). This duplex assay should provide useful information for patient-oriented management and clinical decision-making in CHC. Full article

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Open AccessArticle Polymorphisms in the LPL and CETP Genes and Haplotype in the ESR1 Gene Are Associated with Metabolic Syndrome in Women from Southwestern Mexico

by José Ángel Cahua-Pablo, Miguel Cruz, Abigail Méndez-Palacios, Diana Lizzete Antúnez-Ortiz, Amalia Vences-Velázquez, Luz del Carmen Alarcón-Romero, Esteban Juan Parra, Vianet Argelia Tello-Flores, Marco Antonio Leyva-Vázquez, Adán Valladares-Salgado, Claudia Paola Pérez-Macedonio and Eugenia Flores-Alfaro

Int. J. Mol. Sci. 2015, 16(9), 21539-21554; doi:10.3390/ijms160921539

Received: 8 June 2015 / Revised: 20 July 2015 / Accepted: 24 July 2015 / Published: 8 September 2015

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Abstract

Metabolic syndrome (MetS) is a combination of metabolic disorders associated with an increased risk for cardiovascular disease (CVD). Studies in women reported associations between polymorphisms in ESR1, LPL and CETP genes and MetS. Our aim was to evaluate the association between variants

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Metabolic syndrome (MetS) is a combination of metabolic disorders associated with an increased risk for cardiovascular disease (CVD). Studies in women reported associations between polymorphisms in ESR1, LPL and CETP genes and MetS. Our aim was to evaluate the association between variants in ESR1, LPL and CETP genes with MetS and its components. Four hundred and eighty women were analyzed, anthropometric features and biochemical profiles were evaluated, and genotyping was performed by real-time PCR. We found an association with elevated glucose levels (odds ratio (OR) = 2.9; p = 0.013) in carrying the AA genotype of rs1884051 in the ESR1 gene compared with the GG genotype, and the CC genotype of rs328 in the LPL gene was associated with MetS compared to the CG or GG genotype (OR = 2.8; p = 0.04). Moreover, the GA genotype of rs708272 in the CETP gene is associated with MetS compared to the GG or AA genotype (OR = 1.8; p = 0.006). In addition the ACTCCG haplotype in the ESR1 gene is associated with a decrease in the risk of MetS (OR = 0.02; p < 0.001). In conclusion, our results show the involvement of the variants of ESR1, LPL and CETP genes in metabolic events related to MetS or some of its features. Full article

Open AccessArticle SLCO1B1 c.388A>G Polymorphism Is Associated with HDL-C Levels in Response to Atorvastatin in Chilean Individuals

by Yalena Prado, Nicolás Saavedra, Tomás Zambrano, Jenny Lagos, Alexy Rosales and Luis A. Salazar

Int. J. Mol. Sci. 2015, 16(9), 20609-20619; doi:10.3390/ijms160920609

Received: 22 April 2015 / Revised: 20 August 2015 / Accepted: 25 August 2015 / Published: 31 August 2015

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Abstract

The use of statins as the preferred lipid-lowering therapy has clearly demonstrated its efficacy in the treatment of hypercholesterolemia, reducing also the risk of coronary events and cardiovascular disease mortality. In this study, we assessed single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene

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The use of statins as the preferred lipid-lowering therapy has clearly demonstrated its efficacy in the treatment of hypercholesterolemia, reducing also the risk of coronary events and cardiovascular disease mortality. In this study, we assessed single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene and their effect on atorvastatin response. We included 129 Chilean hypercholesterolemic patients undergoing 10 mg/day of atorvastatin therapy during 4 weeks. Lipid profile was determined before and after drug administration. Genotyping of SLCO1B1 rs4149056 (c.521T>C) SNP was performed with allele-specific polymerase chain reaction, whilst polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping the SLCO1B1 rs2306283 (c.388A>G) variant. After statin therapy, concentrations of TC, LDL-C and TG had a decrease from baseline (p < 0.05). Also, HDL-C levels increased (p < 0.05). Minor allele frequencies for the rs2306283 and rs4149056 variants were 0.547 and 0.136, respectively. LDL-C response to atorvastatin was not associated with the SLCO1B1 rs4149056 nor the rs2306283 polymorphisms (p > 0.05). However, the latter SNP was associated with HDL-C variability after atorvastatin medication (p = 0.02). This study indicates that LDL-C reduction following atorvastatin therapy is not influenced by the SNPs evaluated. In addition, the polymorphism rs2306283 at the SLCO1B1 gene determines greater HDL-C concentrations in response to atorvastatin medication in Chilean hypercholesterolemic subjects. Full article

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Open AccessArticle A Single Nucleotide Polymorphism near the CYP17A1 Gene Is Associated with Left Ventricular Mass in Hypertensive Patients under Pharmacotherapy

by Matthias Huber, Susanne Lezius, Rona Reibis, Andras Treszl, Dorota Kujawinska, Stefanie Jakob, Karl Wegscheider, Heinz Völler and Reinhold Kreutz

Int. J. Mol. Sci. 2015, 16(8), 17456-17468; doi:10.3390/ijms160817456

Received: 29 June 2015 / Revised: 16 July 2015 / Accepted: 23 July 2015 / Published: 30 July 2015

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Abstract

Cytochrome P450 17A1 (CYP17A1) catalyses the formation and metabolism of steroid hormones. They are involved in blood pressure (BP) regulation and in the pathogenesis of left ventricular hypertrophy. Therefore, altered function of CYP17A1 due to genetic variants may influence BP and left ventricular

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Cytochrome P450 17A1 (CYP17A1) catalyses the formation and metabolism of steroid hormones. They are involved in blood pressure (BP) regulation and in the pathogenesis of left ventricular hypertrophy. Therefore, altered function of CYP17A1 due to genetic variants may influence BP and left ventricular mass. Notably, genome wide association studies supported the role of this enzyme in BP control. Against this background, we investigated associations between single nucleotide polymorphisms (SNPs) in or nearby the CYP17A1 gene with BP and left ventricular mass in patients with arterial hypertension and associated cardiovascular organ damage treated according to guidelines. Patients (n = 1007, mean age 58.0 ± 9.8 years, 83% men) with arterial hypertension and cardiac left ventricular ejection fraction (LVEF) ≥40% were enrolled in the study. Cardiac parameters of left ventricular mass, geometry and function were determined by echocardiography. The cohort comprised patients with coronary heart disease (n = 823; 81.7%) and myocardial infarction (n = 545; 54.1%) with a mean LVEF of 59.9% ± 9.3%. The mean left ventricular mass index (LVMI) was 52.1 ± 21.2 g/m^2.7 and 485 (48.2%) patients had left ventricular hypertrophy. There was no significant association of any investigated SNP (rs619824, rs743572, rs1004467, rs11191548, rs17115100) with mean 24 h systolic or diastolic BP. However, carriers of the rs11191548 C allele demonstrated a 7% increase in LVMI (95% CI: 1%–12%, p = 0.017) compared to non-carriers. The CYP17A1 polymorphism rs11191548 demonstrated a significant association with LVMI in patients with arterial hypertension and preserved LVEF. Thus, CYP17A1 may contribute to cardiac hypertrophy in this clinical condition. Full article

Open AccessArticle Association between the NF-E2 Related Factor 2 Gene Polymorphism and Oxidative Stress, Anti-Oxidative Status, and Newly-Diagnosed Type 2 Diabetes Mellitus in a Chinese Population

by Xia Wang, Hongxia Chen, Jun Liu, Yingying Ouyang, Di Wang, Wei Bao and Liegang Liu

Int. J. Mol. Sci. 2015, 16(7), 16483-16496; doi:10.3390/ijms160716483

Received: 21 March 2015 / Revised: 14 June 2015 / Accepted: 30 June 2015 / Published: 20 July 2015

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Abstract

Oxidative stress is a major risk factor in the onset and progression of type 2 diabetes mellitus (T2DM). NF-E2 related factor 2 (NRF2) is a pivotal transcription factor in oxidative stress related illnesses. This study included 2174 subjects with 879 cases

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Oxidative stress is a major risk factor in the onset and progression of type 2 diabetes mellitus (T2DM). NF-E2 related factor 2 (NRF2) is a pivotal transcription factor in oxidative stress related illnesses. This study included 2174 subjects with 879 cases of newly-diagnosed T2DM and 1295 healthy controls. Compared to individuals with the CC genotype, those with the AA genotype had lower total anti-oxidative capacity, superoxide dismutase, catalase, glutathione, glutathione peroxidase activity; and lower homeostasis model assessment of β-cell function index. Those with the AA genotype also had a higher malondialdehyde concentration and homeostasis model assessment of insulin resistance index values. The frequency of allele A was significantly higher in T2DM subjects (29.4%), compared to control subjects (26.1%; p = 0.019). Individuals with the AA genotype had a significantly higher risk of developing T2DM (OR 1.56; 95% CI 1.11, 2.20; p = 0.011), relative to those with the CC genotype, even after adjusting for known T2DM risk factors. Our results suggest that the NRF2 rs6721961 polymorphism was significantly associated with oxidative stress, anti-oxidative status, and risk of newly-diagnosed T2DM. This polymorphism may also contribute to impaired insulin secretory capacity and increased insulin resistance in a Chinese population. Full article

Open AccessComment Alleged Detrimental Mutations in the SMPD1 Gene in Patients with Niemann-Pick Disease

by Cosima Rhein, Christiane Mühle, Johannes Kornhuber and Martin Reichel

Int. J. Mol. Sci. 2015, 16(6), 13649-13652; doi:10.3390/ijms160613649

Received: 5 May 2015 / Revised: 4 June 2015 / Accepted: 8 June 2015 / Published: 15 June 2015

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Abstract

Loss-of-function mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene are associated with decreased catalytic activity of acid sphingomyelinase (ASM) and are the cause of the autosomal recessive lysosomal storage disorder Niemann-Pick disease (NPD) types A and B. Currently, >100 missense mutations

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Loss-of-function mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene are associated with decreased catalytic activity of acid sphingomyelinase (ASM) and are the cause of the autosomal recessive lysosomal storage disorder Niemann-Pick disease (NPD) types A and B. Currently, >100 missense mutations in SMPD1 are listed in the Human Gene Mutation Database. However, not every sequence variation in SMPD1 is detrimental and gives rise to NPD. We have analysed several alleged SMPD1 missense mutations mentioned in a recent publication and found them to be common variants of SMPD1 that give rise to normal in vivo and in vitro ASM activity. (Comment on Manshadi et al. Int. J. Mol. Sci. 2015, 16, 6668–6676). Full article

Open AccessArticle The rs2516839 Polymorphism of the USF1 Gene May Modulate Serum Triglyceride Levels in Response to Cigarette Smoking

by Pawel Niemiec, Tomasz Nowak, Tomasz Iwanicki, Sylwia Gorczynska-Kosiorz, Anna Balcerzyk, Jolanta Krauze, Wladyslaw Grzeszczak, Maria Wiecha and Iwona Zak

Int. J. Mol. Sci. 2015, 16(6), 13203-13216; doi:10.3390/ijms160613203

Received: 4 May 2015 / Revised: 30 May 2015 / Accepted: 1 June 2015 / Published: 10 June 2015

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Abstract

Single nucleotide polymorphisms (SNPs) of the USF1 gene (upstream stimulatory factor 1) influence plasma lipid levels. This study aims to determine whether USF1 SNPs interact with traditional risk factors of atherosclerosis to increase coronary artery disease (CAD) risk. In the present study serum

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Single nucleotide polymorphisms (SNPs) of the USF1 gene (upstream stimulatory factor 1) influence plasma lipid levels. This study aims to determine whether USF1 SNPs interact with traditional risk factors of atherosclerosis to increase coronary artery disease (CAD) risk. In the present study serum lipid levels and USF1 gene polymorphisms (rs2516839 and rs3737787) were determined in 470 subjects: 235 patients with premature CAD and 235 controls. A trend of increasing triglycerides (TG) levels in relation to the C allele dose of rs2516839 SNP was observed. The synergistic effect of cigarette smoking and C allele carrier state on CAD risk was also found (SIM = 2.69, p = 0.015). TG levels differentiated significantly particular genotypes in smokers (1.53 mmol/L for TT, 1.80 mmol/L for CT and 2.27 mmol/L for CC subjects). In contrast, these differences were not observed in the non-smokers subgroup (1.57 mmol/L for TT, 1.46 mmol/L for CT and 1.49 mmol/L for CC subjects). In conclusion, the rs2516839 polymorphism may modulate serum triglyceride levels in response to cigarette smoking. Carriers of the C allele seem to be particularly at risk of CAD, when exposed to cigarette smoking. Full article

Open AccessArticle Are MTHFR C677T and MTRR A66G Polymorphisms Associated with Overweight/Obesity Risk? From a Case-Control to a Meta-Analysis of 30,327 Subjects

by Shu-Jun Fan, Bo-Yi Yang, Xue-Yuan Zhi, Miao He, Da Wang, Yan-Xun Wang, Yi-Nuo Wang, Jian Wei, Quan-Mei Zheng and Gui-Fan Sun

Int. J. Mol. Sci. 2015, 16(6), 11849-11863; doi:10.3390/ijms160611849

Received: 31 March 2015 / Accepted: 15 May 2015 / Published: 26 May 2015

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Abstract

Several studies have examined the associations of methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms with being overweight/obesity. However, the results are still controversial. We therefore conducted a case-control study (517 cases and 741 controls) in

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Several studies have examined the associations of methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms with being overweight/obesity. However, the results are still controversial. We therefore conducted a case-control study (517 cases and 741 controls) in a Chinese Han population and then performed a meta-analysis by combining previous studies (5431 cases and 24,896 controls). In our case-control study, the MTHFR C677T polymorphism was not significantly associated with being overweight/obesity when examining homozygous codominant, heterozygous codominant, dominant, recessive and allelic genetic models. The following meta-analysis confirmed our case-control results. Heterogeneity was minimal in the overall analysis, and sensitivity analyses and publication bias tests indicated that the meta-analytic results were reliable. Similarly, both the case-control study and meta-analysis found no significant association between the MTRR A66G polymorphism and being overweight/obesity. However, sensitivity analyses showed that the associations between the MTRR A66G polymorphism and being overweight/obesity became significant in the dominant, heterozygous codominant and allelic models after excluding our case-control study. The results from our case-control study and meta-analysis suggest that both of the two polymorphisms are not associated with being overweight/obesity. Further large-scale population-based studies, especially for the MTRR A66G polymorphism, are still needed to confirm or refute our findings. Full article

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Open AccessArticle The Influence of PSCA Gene Variation on Its Expression and Gastric Adenocarcinoma Susceptibility in the Northwest Chinese Population

by Wentao Zhang, Ping Liang, Weihua Wang, Peng Dai, Qin Wang, Wei Yan, Jinrong Zhao, Jianbin Sun, Yong Peng, Daxiang Cui and Zhen Yan

Int. J. Mol. Sci. 2015, 16(5), 11648-11658; doi:10.3390/ijms160511648

Received: 30 March 2015 / Revised: 4 May 2015 / Accepted: 11 May 2015 / Published: 21 May 2015

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Abstract

Gastric adenocarcinoma (GAC) imposes a considerable health burden around the world. Gene variation in prostate stem cell antigen gene (PSCA) has been identified to be associated with GAC risk, while the results showed regional variation. To explore the influence of PSCA

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Gastric adenocarcinoma (GAC) imposes a considerable health burden around the world. Gene variation in prostate stem cell antigen gene (PSCA) has been identified to be associated with GAC risk, while the results showed regional variation. To explore the influence of PSCA gene variation on its expression and GAC risk in the Northwest Chinese population, four single nucleotide polymorphisms (SNPs) of PSCA were genotyped in 476 GAC cases and 481 controls using MassARRAY system. Two SNPs of rs2294008 (C>T) and rs2976392 (G>A) were identified to be associated with GAC risk. rs2294008, rs2976392 and rs10216533 made up two statistically significant haplotypes (Hap-CGG and Hap-TAG). Additionally, PSCA expression was analyzed by quantitative real time PCR, immunohistochemistry and tissue microarray. The results showed that PSCA expression was decreased in GAC tissues compared with adjacent normal tissues. For normal tissues, PSCA expression was higher with Hap-TA than that with Hap-CG. For GAC tissues, the differentiation degree of Hap-TA was higher than that of Hap-CG. The expression distribution of PSCA in multiple human organs showed disparity. These results suggest that PSCA gene variation has a potential effect on its expression and GAC risk in the Northwest Chinese population. Full article

Open AccessArticle APOE Polymorphisms Contribute to Reduced Atorvastatin Response in Chilean Amerindian Subjects

by Jenny Lagos, Tomás Zambrano, Alexy Rosales and Luis A. Salazar

Int. J. Mol. Sci. 2015, 16(4), 7890-7899; doi:10.3390/ijms16047890

Received: 19 March 2015 / Revised: 3 April 2015 / Accepted: 3 April 2015 / Published: 9 April 2015

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Abstract

Genetic factors can determine the high variability observed in response to lipid-lowering therapy with statins. Nonetheless, the frequency of single nucleotide polymorphisms (SNPs) and their impact can vary due to ethnicity. Because the Chilean population carries a strong Amerindian background, the objective of

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Genetic factors can determine the high variability observed in response to lipid-lowering therapy with statins. Nonetheless, the frequency of single nucleotide polymorphisms (SNPs) and their impact can vary due to ethnicity. Because the Chilean population carries a strong Amerindian background, the objective of this study was to evaluate the influence of apolipoprotein E (APOE) variants (rs429358, rs7412) and the 1959C>T SNP (rs5925) in the low-density lipoprotein receptor (LDLR) in response to atorvastatin treatment in hypercholesterolemic individuals. A hundred and thirty nine subjects undergoing statin therapy were included. Identification of Amerindian mtDNA haplogroups was determined by polymerase chain reaction (PCR) and PCR followed by restriction fragment length polymorphism (RFLP), respectively. SNPs were determined by PCR-RFLP. Out of the 139 individuals studied, 84.4% had an Amerindian background, according to mtDNA analysis. In relation to APOE variants, carriers of the E3/4 genotype presented lower cholesterol reduction compared to genotype E3/3 (LDL-C: −18% vs. −29%, p ˂ 0.001). On the other hand, the LDLR rs5925 SNP was not related to atorvastatin response (p = 0.5760). Our results suggest that APOE SNPs are potential predictors to atorvastatin therapy in Amerindian Chilean subjects. Full article

Open AccessArticle Genetic Variant in Interleukin-18 Is Associated with Idiopathic Recurrent Miscarriage in Chinese Han Population

by Jun Yue, Yu Tong, Jing Zhou, Qingqing Liu and Jiyun Yang

Int. J. Mol. Sci. 2015, 16(2), 4180-4189; doi:10.3390/ijms16024180

Received: 19 December 2014 / Revised: 23 January 2015 / Accepted: 10 February 2015 / Published: 16 February 2015

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Abstract

Levels of IL-18 were significantly lower in women with recurrent miscarriage (RM) than those without idiopathic RM. IL-18 promoter single nucleotide polymorphisms were previously identified to have an impact on IL18 gene transcription activity and influence the level of IL-18 protein production. The

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Levels of IL-18 were significantly lower in women with recurrent miscarriage (RM) than those without idiopathic RM. IL-18 promoter single nucleotide polymorphisms were previously identified to have an impact on IL18 gene transcription activity and influence the level of IL-18 protein production. The aim of this study was to evaluate whether IL-18 gene polymorphisms are risk factors for idiopathic RM in Chinese Han population. Study subjects comprised of 484 idiopathic RM patients and 468 controls. Three polymorphisms (rs360717, rs187238, rs1946518) in IL-18 gene and serum IL-18 concentrations were assessed. rs187238 variant exhibits significant association with RM in additive and recessive genetic model (additive model p = 1.05 × 10⁻⁴, dominant model p = 0.025, recessive model p = 2.43 × 10⁻⁵). In contrast, rs360717 and rs1946518 are not significantly associated with RM. Serum IL-18 levels are significantly lower in RM cases than in control (111.98 ± 93.13 versus 148.74 ± 130.51 pg/mL, p = 7.42 × 10⁻⁷). There are lower levels of serum IL-18 in rs187238 homozygous mutant (CC) than homozygous wild-type (GG) in this study population, including cases and control groups (98.31 ± 86.46 versus 131.87 ± 115.02 pg/mL, p = 0.015). These results suggest that reduced IL-18 levels and rs187238 variant may contribute to pathogenesis of idiopathic RM in Chinese Han population. Full article

Open AccessReview Pacemaker Activity of the Human Sinoatrial Node: An Update on the Effects of Mutations in HCN4 on the Hyperpolarization-Activated Current

by Arie O. Verkerk and Ronald Wilders

Int. J. Mol. Sci. 2015, 16(2), 3071-3094; doi:10.3390/ijms16023071

Received: 22 December 2014 / Accepted: 22 January 2015 / Published: 29 January 2015

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Abstract

Since 2003, several loss-of-function mutations in the HCN4 gene, which encodes the HCN4 protein, have been associated with sinus node dysfunction. In human sinoatrial node (SAN), HCN4 is the most abundant of the four isoforms of the HCN family. Tetramers of HCN subunits

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Since 2003, several loss-of-function mutations in the HCN4 gene, which encodes the HCN4 protein, have been associated with sinus node dysfunction. In human sinoatrial node (SAN), HCN4 is the most abundant of the four isoforms of the HCN family. Tetramers of HCN subunits constitute the ion channels that conduct the hyperpolarization-activated “funny” current (I_f), which plays an important modulating role in SAN pacemaker activity. Voltage-clamp experiments on HCN4 channels expressed in COS-7, CHO and HEK-293 cells, as well as in Xenopus oocytes have revealed changes in the expression and kinetics of mutant channels, but the extent to which especially the kinetic changes would affect I_f flowing during a human SAN action potential often remains unresolved. In our contribution to the Topical Collection on Human Single Nucleotide Polymorphisms and Disease Diagnostics, we provide an updated review of the mutation-induced changes in the expression and kinetics of HCN4 channels and provide an overview of their effects on I_f during the time course of a human SAN action potential, as assessed in simulated action potential clamp experiments. Future research may solve apparent inconsistencies between data from clinical studies and data from in vitro and in silico experiments. Full article

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Open AccessArticle The Association of ADORA2A and ADORA2B Polymorphisms with the Risk and Severity of Chronic Heart Failure: A Case-Control Study of a Northern Chinese Population

by Ya-Jing Zhai, Ping Liu, Hai-Rong He, Xiao-Wei Zheng, Yan Wang, Qian-Ting Yang, Ya-Lin Dong and Jun Lu

Int. J. Mol. Sci. 2015, 16(2), 2732-2746; doi:10.3390/ijms16022732

Received: 18 December 2014 / Accepted: 22 January 2015 / Published: 26 January 2015

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Abstract

The causes of chronic heart failure (CHF) and its progression are likely to be due to complex genetic factors. Adenosine receptors A2A and A2B (ADORA2A and ADORA2B, respectively) play an important role in cardio-protection. Therefore, polymorphisms in the genes encoding those receptors may

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The causes of chronic heart failure (CHF) and its progression are likely to be due to complex genetic factors. Adenosine receptors A2A and A2B (ADORA2A and ADORA2B, respectively) play an important role in cardio-protection. Therefore, polymorphisms in the genes encoding those receptors may affect the risk and severity of CHF. This study was a case-control comparative investigation of 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls. Four common single-nucleotide polymorphisms (SNPs) of ADORA2A (rs2236625, rs2236624, rs4822489, and rs5751876) and one SNP of ADORA2B (rs7208480) were genotyped and an association between SNPs and clinical outcomes was evaluated. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association. The rs4822489 was significantly associated with the severity of CHF after adjustment for traditional cardiovascular risk factors (p = 0.040, OR = 1.912, 95% CI = 1.029–3.550). However, the five SNPs as well as the haplotypes were not found to be associated with CHF susceptibility. The findings of this study suggest that rs4822489 may contribute to the severity of CHF in the northern Chinese. However, further studies performed in larger populations and aimed at better defining the role of this gene are required. Full article

Open AccessArticle Factor XIII B Subunit Polymorphisms and the Risk of Coronary Artery Disease

by Zoltán A. Mezei, Zsuzsanna Bereczky, Éva Katona, Réka Gindele, Emília Balogh, Szilvia Fiatal, László Balogh, István Czuriga, Róza Ádány, István Édes and László Muszbek

Int. J. Mol. Sci. 2015, 16(1), 1143-1159; doi:10.3390/ijms16011143

Received: 8 November 2014 / Accepted: 26 December 2014 / Published: 6 January 2015

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Abstract

The aim of the case-control study was to explore the effect of coagulation factor XIII (FXIII) B subunit (FXIII-B) polymorphisms on the risk of coronary artery disease, and on FXIII levels. In the study, 687 patients admitted for coronary angiography to investigate suspected

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The aim of the case-control study was to explore the effect of coagulation factor XIII (FXIII) B subunit (FXIII-B) polymorphisms on the risk of coronary artery disease, and on FXIII levels. In the study, 687 patients admitted for coronary angiography to investigate suspected coronary artery disease and 994 individuals representing the Hungarian population were enrolled. The patients were classified according to the presence of significant coronary atherosclerosis (CAS) and history of myocardial infarction (MI). The F13B gene was genotyped for p.His95Arg and for intron K nt29756 C>G polymorphisms; the latter results in the replacement of 10 C-terminal amino acids by 25 novel amino acids. The p.His95Arg polymorphism did not influence the risk of CAS or MI. The FXIII-B intron K nt29756 G allele provided significant protection against CAS and MI in patients with a fibrinogen level in the upper tertile. However, this effect prevailed only in the presence of the FXIII-A Leu34 allele, and a synergism between the two polymorphisms was revealed. Carriers of the intron K nt29756 G allele had significantly lower FXIII levels, and FXIII levels in the lower tertile provided significant protection against MI. It is suggested that the protective effect of the combined polymorphisms is related to decreased FXIII levels. Full article

Open AccessArticle Cloud Computing-Based TagSNP Selection Algorithm for Human Genome Data

by Che-Lun Hung, Wen-Pei Chen, Guan-Jie Hua, Huiru Zheng, Suh-Jen Jane Tsai and Yaw-Ling Lin

Int. J. Mol. Sci. 2015, 16(1), 1096-1110; doi:10.3390/ijms16011096

Received: 16 September 2014 / Accepted: 4 December 2014 / Published: 5 January 2015

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Abstract

Single nucleotide polymorphisms (SNPs) play a fundamental role in human genetic variation and are used in medical diagnostics, phylogeny construction, and drug design. They provide the highest-resolution genetic fingerprint for identifying disease associations and human features. Haplotypes are regions of linked genetic variants

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Single nucleotide polymorphisms (SNPs) play a fundamental role in human genetic variation and are used in medical diagnostics, phylogeny construction, and drug design. They provide the highest-resolution genetic fingerprint for identifying disease associations and human features. Haplotypes are regions of linked genetic variants that are closely spaced on the genome and tend to be inherited together. Genetics research has revealed SNPs within certain haplotype blocks that introduce few distinct common haplotypes into most of the population. Haplotype block structures are used in association-based methods to map disease genes. In this paper, we propose an efficient algorithm for identifying haplotype blocks in the genome. In chromosomal haplotype data retrieved from the HapMap project website, the proposed algorithm identified longer haplotype blocks than an existing algorithm. To enhance its performance, we extended the proposed algorithm into a parallel algorithm that copies data in parallel via the Hadoop MapReduce framework. The proposed MapReduce-paralleled combinatorial algorithm performed well on real-world data obtained from the HapMap dataset; the improvement in computational efficiency was proportional to the number of processors used. Full article

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Open AccessArticle Association between ADIPOQ +45T>G Polymorphism and Type 2 Diabetes: A Systematic Review and Meta-Analysis

by Yaofu Fan, Kun Wang, Shuhang Xu, Guofang Chen, Hongjie Di, Meng Cao and Chao Liu

Int. J. Mol. Sci. 2015, 16(1), 704-723; doi:10.3390/ijms16010704

Received: 6 October 2014 / Accepted: 18 December 2014 / Published: 30 December 2014

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Abstract

Recently, a number of studies have reported the association between the single nucleotide polymorphisms (SNPs) +45T>G polymorphism in the adiponectin (ADIPOQ) gene and type 2 diabetes mellitus (T2DM) risk, though the results are inconsistent. In order to obtain a more precise estimation of

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Recently, a number of studies have reported the association between the single nucleotide polymorphisms (SNPs) +45T>G polymorphism in the adiponectin (ADIPOQ) gene and type 2 diabetes mellitus (T2DM) risk, though the results are inconsistent. In order to obtain a more precise estimation of the relationship, a meta-analysis was performed. In this current study, the Medline, Embase, Pubmed, ISI Web of Knowledge, Ovid, Science Citation Index Expanded Database, Wanfang Database, and China National Knowledge Infrastructure were searched for eligible studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of association. Forty-five publications were included in the final meta-analysis with 9986 T2DM patients and 16,222 controls for ADIPOQ +45T>G polymorphism according to our inclusion and exclusion criteria. The +45T>G polymorphism was associated with an overall significantly increased risk of T2DM (G vs. T: OR = 1.18, 95% CI = 1.06–1.32; The dominant model: OR = 1.18, 95% CI = 1.03–1.33; The recessive model: OR = 1.47, 95% CI = 1.20–1.78; The homozygous model: OR = 1.62, 95% CI = 1.25–2.09; Except the heterozygous model: OR = 1.11, 95% CI = 0.98–1.24). Subgroup analysis revealed a significant association between the +45T>G polymorphism and T2D in an Asian population. Thus, this meta-analysis indicates that the G allele of the ADIPOQ +45T>G polymorphisms associated with a significantly increased risk of T2DM in the Asian population. Full article

Open AccessArticle Associations between Variants in IL-33/ST2 Signaling Pathway Genes and Coronary Heart Disease Risk

by Fangqin Wu, Mei'an He, Qiang Wen, Wencai Zhang, Jinhua Yang, Xiaomin Zhang, Tangchun Wu and Longxian Cheng

Int. J. Mol. Sci. 2014, 15(12), 23227-23239; doi:10.3390/ijms151223227

Received: 25 October 2014 / Revised: 2 December 2014 / Accepted: 5 December 2014 / Published: 15 December 2014

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Abstract

The IL-33/ST2 signaling pathway plays an important role in coronary artery disease (CHD); however, few studies have explored how variants in IL-33/ST2 genes influence CHD risk. Here, we examined the association between genetic variants in IL-33, ST2, and IL-1RAcP of the

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The IL-33/ST2 signaling pathway plays an important role in coronary artery disease (CHD); however, few studies have explored how variants in IL-33/ST2 genes influence CHD risk. Here, we examined the association between genetic variants in IL-33, ST2, and IL-1RAcP of the IL-33/ST2 axis and the risk of CHD. We conducted a case-controlled study with 1146 CHD cases and 1146 age- and sex-frequency-matched controls. Twenty-eight single nucleotide polymorphisms (SNPs) in IL-33, ST2, and IL-1RAcP were genotyped by Sequenom MassArray and TaqMan assay. Logistic regression was used to analyze these associations. The SNP rs4624606 in IL-1RAcP was nominally associated with CHD risk. The AA genotype was associated with a 1.85-fold increased risk of CHD (95% confidence interval (CI) = 1.01–3.36; p = 0.045) compared to the TT genotype. Further analysis showed that AA carriers also had a higher risk of CHD than TT + TA carriers (odds ratio (OR) = 1.85; 95% CI = 1.85–3.35; p = 0.043). However, no significant association was observed between variants in IL-33/ST2 genes and CHD risk. Further studies are needed to replicate our results in other ethnic groups with larger sample size. Full article

Open AccessArticle Associations of NR5A2 Gene Polymorphisms with the Clinicopathological Characteristics and Survival of Gastric Cancer

by Xunlei Zhang, Dongying Gu, Mulong Du, Meilin Wang, Chunxiang Cao, Lili Shen, Meng Kuang, Yongfei Tan, Xinying Huo, Weida Gong, Zhi Xu, Jinfei Chen, Zhengdong Zhang and Cuiju Tang

Int. J. Mol. Sci. 2014, 15(12), 22902-22917; doi:10.3390/ijms151222902

Received: 22 September 2014 / Revised: 15 October 2014 / Accepted: 16 November 2014 / Published: 10 December 2014

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Abstract

The orphan nuclear receptor (NR5A2), which belongs to the NR5A subfamily of nuclear receptors, is expressed in developing and adult tissues of endodermal origin, and can contribute to the development of several cancers through regulating cell proliferation. NR5A2 (rs3790843 and rs3790844) single nucleotide

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The orphan nuclear receptor (NR5A2), which belongs to the NR5A subfamily of nuclear receptors, is expressed in developing and adult tissues of endodermal origin, and can contribute to the development of several cancers through regulating cell proliferation. NR5A2 (rs3790843 and rs3790844) single nucleotide polymorphisms (SNPs) genotyping were examined in DNA samples, extracted from paraffin-embedded cancer tissue. Clinicopathologic and follow-up data were collected from 944 patients with gastric cancer (GC). Associations of the 2 SNPs with the progression and prognosis in gastric cancer patients were analyzed using the SPSS version 18.0. We found that NR5A2 rs3790843 polymorphism was significantly associated with the risk of GC which had regional lymph node metastasis (p = 0.044) or distant metastasis (p = 0.020). Our results also indicated that rs3790844 polymorphism was associated with the increased overall survival (OS) of GC patients in the dominant model (GG vs. GA/AA, HR (hazard ratio) = 0.823, 95% CI (confidence interval) = 0.679–0.997), suggesting a potential protective role of the variant A allele. Additionally, in the stratified analysis, both NR5A2 rs3790843 and rs3790844 polymorphism were associated with significantly lower risk of death in the groups of female, tumor size >5 cm in a dominant model. Our results represent the first demonstration that the NR5A2 rs3790844 polymorphism is associated with increased OS of GC patients in the dominant model, and similar results were found among the female group and tumor size >5 cm group for NR5A2 rs3790843 polymorphism. Further validation in other larger studies with different ethnic populations and functional evaluations are needed. Full article

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Open AccessArticle Risk-Association of DNMT1 Gene Polymorphisms with Coronary Artery Disease in Chinese Han Population

by Chunyan Peng, Qianyun Deng, Zuhua Li, Chenling Xiong, Cong Li and Fang Zheng

Int. J. Mol. Sci. 2014, 15(12), 22694-22705; doi:10.3390/ijms151222694

Received: 10 October 2014 / Revised: 27 November 2014 / Accepted: 28 November 2014 / Published: 8 December 2014

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Abstract

Recently, a significant epigenetic component in the pathogenesis of Coronary Artery Disease (CAD) has been realized. Here, we evaluated the possible association of candidate Single Nucleotide Polymorphisms (SNPs) in the epigenetic-regulatory gene, DNA methyltransferase 1 (DNMT1), with CAD in Chinese Han

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Recently, a significant epigenetic component in the pathogenesis of Coronary Artery Disease (CAD) has been realized. Here, we evaluated the possible association of candidate Single Nucleotide Polymorphisms (SNPs) in the epigenetic-regulatory gene, DNA methyltransferase 1 (DNMT1), with CAD in Chinese Han population. Five tag SNPs (rs16999593, rs2336691, rs2228611, rs4804494, rs7253062) were analyzed by High Resolution Melt (HRM) method in 476 CAD patients and 478 controls. Overall, there were significant differences in the genotype and allele distributions of rs2228611 and rs2336691, between patients and controls. The minor A allele of rs2228611 was associated with a lower risk of CAD (p = 0.034); modest effect in the additive analysis but also marginal significance was found in the recessive model [OR_additive = 0.404 (0.184, 0.884), p = 0.023 and OR_recessive = 0.452 (0.213, 0.963), p = 0.040] after adjusting for confounders. While the rs2336691 A allele were associated with a higher risk of developing CAD (p = 0.037); borderline significant association in both additive and dominant models [OR_additive= 1.632 (1.030, 2.583), p = 0.037 and OR_dominant = 1.599 (1.020, 2.507), p = 0.040]. In conclusion, these data provide the first evidence that occurrence of CAD may be moderated by genetic variation in the gene involved in the epigenetic machinery. Full article

Open AccessArticle Variants of the Low Oxygen Sensors EGLN1 and HIF-1AN Associated with Acute Mountain Sickness

by Enhao Zhang, Jihang Zhang, Jun Jin, Jun Qin, Huijie Li and Lan Huang

Int. J. Mol. Sci. 2014, 15(12), 21777-21787; doi:10.3390/ijms151221777

Received: 18 October 2014 / Revised: 17 November 2014 / Accepted: 18 November 2014 / Published: 26 November 2014

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Abstract

Two low oxygen sensors, Egl nine homolog 1 (EGLN1) and hypoxia-inducible factor 1-α inhibitor (HIF-1AN), play pivotal roles in the regulation of HIF-1α, and high altitude adaption may be involved in the pathology of acute mountain sickness (AMS). Here, we aimed to analyze

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Two low oxygen sensors, Egl nine homolog 1 (EGLN1) and hypoxia-inducible factor 1-α inhibitor (HIF-1AN), play pivotal roles in the regulation of HIF-1α, and high altitude adaption may be involved in the pathology of acute mountain sickness (AMS). Here, we aimed to analyze single nucleotide polymorphisms (SNPs) in the untranslated regions of the EGLN1 and HIF-1AN genes and SNPs chosen from a genome-wide adaptation study of the Han Chinese population. To assess the association between EGLN1 and HIF-1AN SNPs and AMS in a Han Chinese population, a case–control study was performed including 190 patients and 190 controls. In total, thirteen SNPs were genotyped using the MassARRAY^® MALDI-TOF system. Multiple genetic models were tested; The Akaike’s information criterion (AIC) and Bayesian information criterion (BIC) values indicated that the dominant model may serve as the best-fit model for rs12406290 and rs2153364 of significant difference. However, these data were not significant after Bonferroni correction. No significant association was noted between AMS and rs12757362, rs1339894, rs1361384, rs2009873, rs2739513 or rs2486729 before and after Bonferroni correction. Further haplotype analyses indicated the presence of two blocks in EGLN1; one block consists of rs12406290-rs2153364, located upstream of the EGLN1 gene. Carriers of the “GG” haplotype of rs12406290-rs2153364 exhibited an increased risk of AMS after adjustments for age and smoking status. However, no significant association was observed among HIF-1AN 3'-untranslated region (3'-UTR) polymorphisms, haplotype and AMS. Our study indicates that variants in the EGLN1 5'-UTR influence the susceptibility to AMS in a Han Chinese population. Full article

Open AccessArticle Associations of MTHFR C677T and MTRR A66G Gene Polymorphisms with Metabolic Syndrome: A Case-Control Study in Northern China

by Boyi Yang, Shujun Fan, Xueyuan Zhi, Da Wang, Yongfang Li, Yinuo Wang, Yanxun Wang, Jian Wei, Quanmei Zheng and Guifan Sun

Int. J. Mol. Sci. 2014, 15(12), 21687-21702; doi:10.3390/ijms151221687

Received: 21 September 2014 / Revised: 3 November 2014 / Accepted: 12 November 2014 / Published: 25 November 2014

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Abstract

Prior evidence indicates that homocysteine plays a role in the development of metabolic syndrome (MetS). Methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms are common genetic determinants of homocysteine levels. To investigate the associations of the

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Prior evidence indicates that homocysteine plays a role in the development of metabolic syndrome (MetS). Methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms are common genetic determinants of homocysteine levels. To investigate the associations of the MTHFR C677T and MTRR A66G polymorphisms with MetS, 692 Chinese Han subjects with MetS and 878 controls were recruited. The component traits of MetS and the MTHFR C677T and MTRR A66G genotypes were determined. A significant association was observed between the MTHFR 677T allele and increased risk of MetS, high fasting blood glucose, high waist circumference, and increasing number of MetS components. The MTRR A66G polymorphism was associated with an increased risk of MetS when combined with the MTHFR 677TT genotype, although there was no association found between MetS and MTRR A66G alone. Furthermore, the MTRR 66GG genotype was associated with high fasting blood glucose and triglycerides. Our data suggest that the MTHFR 677T allele may contribute to an increased risk of MetS in the northern Chinese Han population. The MTRR A66G polymorphism is not associated with MetS. However, it may exacerbate the effect of the MTHFR C677T variant alone. Further large prospective population-based studies are required to confirm our findings. Full article

Open AccessArticle Genetic Variations rs11892031 and rs401681 Are Associated with Bladder Cancer Risk in a Chinese Population

by Yu Zhang, Yan Sun, Tao Chen, Hailong Hu, Wanqin Xie, Zhihui Qiao, Na Ding, Linguo Xie, Sheng Li, Wenlong Wang, Chen Xing, Yihan Wang, Yunkai Qie and Changli Wu

Int. J. Mol. Sci. 2014, 15(11), 19330-19341; doi:10.3390/ijms151119330

Received: 5 September 2014 / Revised: 13 October 2014 / Accepted: 15 October 2014 / Published: 24 October 2014

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Abstract

Genome-wide association studies (GWAS) have identified a number of genetic variants associated with risk of bladder cancer in populations of European descent. Here, we assessed association of two of these variants, rs11892031 (2q37.1 region) and rs401681 (5p15.33 region) in a Chinese case-control study,

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Genome-wide association studies (GWAS) have identified a number of genetic variants associated with risk of bladder cancer in populations of European descent. Here, we assessed association of two of these variants, rs11892031 (2q37.1 region) and rs401681 (5p15.33 region) in a Chinese case-control study, which included 367 bladder cancer cases and 420 controls. We found that the AC genotype of rs11892031 was associated with remarkably decreased risk of bladder cancer (adjusted odds ratio (OR), 0.27; 95% confidence interval (CI), 0.09–0.81; p = 0.019), compared with the AA genotype of rs11892031; and that CT/CC genotypes of rs401681 were associated with significantly increased risk of bladder cancer (adjusted OR, 1.79; 95% CI, 1.10–2.91; p = 0.02), compared with the TT genotype of rs401681. We further conducted stratification analysis to examine the correlation between single nucleotide polymorphism (SNP) rs11892031/rs401681 and tumor grade/stage. Results showed that heterogeneity in ORs of tumor categories was not significant for either rs11892031 or rs401681 (p > 0.05), indicating that the two SNPs seemingly do not associate with tumor grade and stage of bladder cancer in our study population. The present study suggests that the SNPs rs11892031 and rs401681 are associated with bladder cancer risk in a Chinese population. Future analyses will be conducted with more participants recruited in a case-control study. Full article

Open AccessArticle Hope for GWAS: Relevant Risk Genes Uncovered from GWAS Statistical Noise

by Catarina Correia, Yoan Diekmann, Astrid M. Vicente and José B. Pereira-Leal

Int. J. Mol. Sci. 2014, 15(10), 17601-17621; doi:10.3390/ijms151017601

Received: 30 April 2014 / Revised: 1 September 2014 / Accepted: 22 September 2014 / Published: 29 September 2014

Cited by 1 | PDF Full-text (2087 KB) | HTML Full-text | XML Full-text | Supplementary Files

Abstract

Hundreds of genetic variants have been associated to common diseases through genome-wide association studies (GWAS), yet there are limits to current approaches in detecting true small effect risk variants against a background of false positive findings. Here we addressed the missing heritability problem,

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Hundreds of genetic variants have been associated to common diseases through genome-wide association studies (GWAS), yet there are limits to current approaches in detecting true small effect risk variants against a background of false positive findings. Here we addressed the missing heritability problem, aiming to test whether there are indeed risk variants within GWAS statistical noise and to develop a systematic strategy to retrieve these hidden variants. Employing an integrative approach, which combines protein-protein interactions with association data from GWAS for 6 common diseases, we found that associated-genes at less stringent significance levels (p < 0.1) with any of these diseases are functionally connected beyond noise expectation. This functional coherence was used to identify disease-relevant subnetworks, which were shown to be enriched in known genes, outperforming the selection of top GWAS genes. As a proof of principle, we applied this approach to breast cancer, supporting well-known breast cancer genes, while pinpointing novel susceptibility genes for experimental validation. This study reinforces the idea that GWAS are under-analyzed and that missing heritability is rather hidden. It extends the use of protein networks to reveal this missing heritability, thus leveraging the large investment in GWAS that produced so far little tangible gain. Full article

Open AccessArticle The Adenosine Deaminase Gene Polymorphism Is Associated with Chronic Heart Failure Risk in Chinese

by Hai-Rong He, Yuan-Jie Li, Gong-Hao He, Ya-Jun Wang, Ya-Jing Zhai, Jiao Xie, Wei-Peng Zhang, Ya-Lin Dong and Jun Lu

Int. J. Mol. Sci. 2014, 15(9), 15259-15271; doi:10.3390/ijms150915259

Received: 17 July 2014 / Revised: 19 August 2014 / Accepted: 22 August 2014 / Published: 28 August 2014

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Abstract

Adenosine (Ado) is an important cardioprotective agent. Since endogenous Ado levels are affected by the enzyme Ado deaminase (ADA), polymorphisms within the ADA gene may exert some effect on chronic heart failure (CHF). This study applied a case-control investigation to 300 northern Chinese

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Adenosine (Ado) is an important cardioprotective agent. Since endogenous Ado levels are affected by the enzyme Ado deaminase (ADA), polymorphisms within the ADA gene may exert some effect on chronic heart failure (CHF). This study applied a case-control investigation to 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls in which nine single-nucleotide polymorphisms (SNPs) of ADA were genotyped and association analyses were performed. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the association. Overall, rs452159 polymorphism in ADA gene was significantly associated with susceptibility to CHF under the dominant model (p = 0.013, OR = 1.537, 95% CI = 1.10–2.16), after adjustment for age, sex, and traditional cardiovascular risk factors. No difference in genotype distribution and allele frequency for the rs452159 according to the functional New York Heart Association class was found. Furthermore, the values of left ventricular ejection fraction, left-ventricle end-diastolic diameter or left-ventricle end-systolic diameter did not differ significantly among the different rs452159 genotype CHF patients. Although further studies with larger cohorts and other ethnicities are required to validate the conclusions, the findings of this study potentially provide novel insight into the pathogenesis of CHF. Full article

Open AccessReview Non-Synonymous Single Nucleotide Polymorphisms in the P2X Receptor Genes: Association with Diseases, Impact on Receptor Functions and Potential Use as Diagnosis Biomarkers

by Emily A. Caseley, Stephen P. Muench, Sebastien Roger, Hong-Ju Mao, Stephen A. Baldwin and Lin-Hua Jiang

Int. J. Mol. Sci. 2014, 15(8), 13344-13371; doi:10.3390/ijms150813344

Received: 6 June 2014 / Revised: 10 July 2014 / Accepted: 14 July 2014 / Published: 30 July 2014

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Abstract

P2X receptors are Ca²⁺-permeable cationic channels in the cell membranes, where they play an important role in mediating a diversity of physiological and pathophysiological functions of extracellular ATP. Mammalian cells express seven P2X receptor genes. Single nucleotide polymorphisms (SNPs) are widespread

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P2X receptors are Ca²⁺-permeable cationic channels in the cell membranes, where they play an important role in mediating a diversity of physiological and pathophysiological functions of extracellular ATP. Mammalian cells express seven P2X receptor genes. Single nucleotide polymorphisms (SNPs) are widespread in the P2RX genes encoding the human P2X receptors, particularly the human P2X7 receptor. This article will provide an overview of the non-synonymous SNPs (NS-SNPs) that have been associated with or implicated in altering the susceptibility to pathologies or disease conditions, and discuss the consequences of the mutations resulting from such NS-SNPs on the receptor functions. Disease-associated NS-SNPs in the P2RX genes have been valuable in understanding the disease etiology and the receptor function, and are promising as biomarkers to be used for the diagnosis and development of stratified therapeutics. Full article

Open AccessArticle Bioinformatics Study of Cancer-Related Mutations within p53 Phosphorylation Site Motifs

by Xiaona Ji, Qiang Huang, Long Yu, Ruth Nussinov and Buyong Ma

Int. J. Mol. Sci. 2014, 15(8), 13275-13298; doi:10.3390/ijms150813275

Received: 10 June 2014 / Revised: 23 July 2014 / Accepted: 24 July 2014 / Published: 29 July 2014

Cited by 3 | PDF Full-text (4027 KB) | HTML Full-text | XML Full-text

Abstract

p53 protein has about thirty phosphorylation sites located at the N- and C-termini and in the core domain. The phosphorylation sites are relatively less mutated than other residues in p53. To understand why and how p53 phosphorylation sites are rarely mutated

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p53 protein has about thirty phosphorylation sites located at the N- and C-termini and in the core domain. The phosphorylation sites are relatively less mutated than other residues in p53. To understand why and how p53 phosphorylation sites are rarely mutated in human cancer, using a bioinformatics approaches, we examined the phosphorylation site and its nearby flanking residues, focusing on the consensus phosphorylation motif pattern, amino-acid correlations within the phosphorylation motifs, the propensity of structural disorder of the phosphorylation motifs, and cancer mutations observed within the phosphorylation motifs. Many p53 phosphorylation sites are targets for several kinases. The phosphorylation sites match 17 consensus sequence motifs out of the 29 classified. In addition to proline, which is common in kinase specificity-determining sites, we found high propensity of acidic residues to be adjacent to phosphorylation sites. Analysis of human cancer mutations in the phosphorylation motifs revealed that motifs with adjacent acidic residues generally have fewer mutations, in contrast to phosphorylation sites near proline residues. p53 phosphorylation motifs are mostly disordered. However, human cancer mutations within phosphorylation motifs tend to decrease the disorder propensity. Our results suggest that combination of acidic residues Asp and Glu with phosphorylation sites provide charge redundancy which may safe guard against loss-of-function mutations, and that the natively disordered nature of p53 phosphorylation motifs may help reduce mutational damage. Our results further suggest that engineering acidic amino acids adjacent to potential phosphorylation sites could be a p53 gene therapy strategy. Full article

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Open AccessArticle Effects of β2-Adrenergic Receptor Gene Polymorphisms on Ritodrine Therapy in Pregnant Women with Preterm Labor: Prospective Follow-Up Study

by Jin Young Park, Na Ra Lee, Kyung Eun Lee, Sunny Park, Young Ju Kim and Hye Sun Gwak

Int. J. Mol. Sci. 2014, 15(7), 12885-12894; doi:10.3390/ijms150712885

Received: 27 May 2014 / Revised: 25 June 2014 / Accepted: 11 July 2014 / Published: 21 July 2014

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Abstract

This study aimed to evaluate the effects of β2-adrenergic receptor (ADRB2) gene polymorphisms on ritodrine therapy outcomes in patients with preterm labor. Genotyping analysis of ADRB2 gene (rs1042713, rs1042714, rs1042717, rs1042718, and rs1042719) was performed on 137 patients with preterm

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This study aimed to evaluate the effects of β2-adrenergic receptor (ADRB2) gene polymorphisms on ritodrine therapy outcomes in patients with preterm labor. Genotyping analysis of ADRB2 gene (rs1042713, rs1042714, rs1042717, rs1042718, and rs1042719) was performed on 137 patients with preterm labor. Survival analysis was conducted for the effects of SNPs on the median time to delivery as a primary outcome. The median time to delivery in the study patients was 349.3 h. Gestational age at admission and modified Bishop scores revealed significant effects on time to delivery (p < 0.001). Among studied SNPs, rs1042717 and rs1042718 showed linkage disequilibrium in this population, and their effects on time to delivery were marginally significant (p < 0.1). Patients with variant-homozygotes in the rs1042713 showed considerably shortened time to delivery compared to wild-allele carriers. The rs1042719 polymorphism significantly affected time to delivery in both univariate and multivariate analysis; the GC and CC carriers showed 64% decrease in time to delivery compared to the wild-type homozygote carriers. Based on the results, it was concluded that the gene polymorphisms of ADRB2 could affect ritodrine therapy in patients with preterm labor. However, given the single-center and the relatively small sample size, our hypothesis requires further independent validation using multi-center and large sample size. Full article

Open AccessArticle Novel and Functional DNA Sequence Variants within the GATA6 Gene Promoter in Ventricular Septal Defects

by Chunyu Li, Xianke Li, Shuchao Pang, Wei Chen, Xianyun Qin, Wenhui Huang, Changqing Zeng and Bo Yan

Int. J. Mol. Sci. 2014, 15(7), 12677-12687; doi:10.3390/ijms150712677

Received: 29 April 2014 / Revised: 16 June 2014 / Accepted: 8 July 2014 / Published: 17 July 2014

Cited by 3 | PDF Full-text (1068 KB) | HTML Full-text | XML Full-text

Abstract

Congenital heart disease (CHD) is the most common birth defect in humans. Genetic causes and underlying molecular mechanisms for isolated CHD remain largely unknown. Studies have demonstrated that GATA transcription factor 6 (GATA6) plays an essential role in the heart development.

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Congenital heart disease (CHD) is the most common birth defect in humans. Genetic causes and underlying molecular mechanisms for isolated CHD remain largely unknown. Studies have demonstrated that GATA transcription factor 6 (GATA6) plays an essential role in the heart development. Mutations in GATA6 gene have been associated with diverse types of CHD. As GATA6 functions in a dosage-dependent manner, we speculated that changed GATA6 levels, resulting from DNA sequence variants (DSVs) within the gene regulatory regions, may mediate the CHD development. In the present study, GATA6 gene promoter was genetically and functionally analyzed in large groups of patients with ventricular septal defect (VSD) (n = 359) and ethnic-matched healthy controls (n = 365). In total, 11 DSVs, including four SNPs, were identified in VSD patients and controls. Two novel and heterozygous DSVs, g.22169190A>T and g.22169311C>G, were identified in two VSD patients, but in none of controls. In cultured cardiomyocytes, the activities of the GATA6 gene promoter were significantly reduced by the DSVs g.22169190A>T and g.22169311C>G. Therefore, our findings suggested that the DSVs within the GATA6 gene promoter identified in VSD patients may change GATA6 levels, contributing to the VSD development as a risk factor. Full article

Open AccessArticle Role of EZH2 Polymorphisms in Esophageal Squamous Cell Carcinoma Risk in Han Chinese Population

by Zhen-Bin Ma, Guang-Hong Guo, Qiong Niu and Ning Shi

Int. J. Mol. Sci. 2014, 15(7), 12688-12697; doi:10.3390/ijms150712688

Received: 28 May 2014 / Revised: 5 July 2014 / Accepted: 8 July 2014 / Published: 17 July 2014

Cited by 4 | PDF Full-text (727 KB) | HTML Full-text | XML Full-text

Abstract

Gene single nucleotide polymorphisms play a critical role in the development of esophageal squamous cell carcinoma (ESCC). The aim of this study is to investigate the associations between EZH2 gene polymorphisms and ESCC risk. We undertook a case-control study to analyze three EZH2

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Gene single nucleotide polymorphisms play a critical role in the development of esophageal squamous cell carcinoma (ESCC). The aim of this study is to investigate the associations between EZH2 gene polymorphisms and ESCC risk. We undertook a case-control study to analyze three EZH2 polymorphisms (148505302C > T, 2110 + 6A > C and 626 − 394T > C) in an Han Chinese population, by extraction of genomic DNA from the peripheral blood of 476 patients with ESCC and 492 control participants, and performed EZH2 genotyping using DNA sequencing. The obtained results indicated that overall, no statistically significant association was observed in 148505302C > T and 2110 + 6A > C. However, 626 − 394T > C genotype was at increased risk of ESCCs (p = 0.006; odds ratio (OR) = 1.131, CI 95%: 1.034–1.236). Moreover, 626 − 394C/C genotype ESCCs were more significantly common in patients with tumor size of >5 cm than T allele ESCC and in cases of poor differentiation and lower advanced pathological stage. In conclusion, polymorphism in 626 − 394T > C was observed to be associated with susceptibility of ESCC. Nevertheless, further investigation with a larger sample size is needed to support our results. Full article

Open AccessArticle A Disease Marker for Aspirin-Induced Chronic Urticaria

by Chia-Wei Hsieh, Jeen-Wei Lee, En-Chih Liao and Jaw-Ji Tsai

Int. J. Mol. Sci. 2014, 15(7), 12591-12603; doi:10.3390/ijms150712591

Received: 20 April 2014 / Revised: 21 May 2014 / Accepted: 21 June 2014 / Published: 15 July 2014

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Abstract

There are currently no diagnostic methods in vitro for aspirin-induced chronic urticaria (AICU) except for the provocation test in vivo. To identify disease markers for AICU, we investigated the single nucleotide polymorphism (SNP) of the promoter loci of high-affinity IgE receptor (

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There are currently no diagnostic methods in vitro for aspirin-induced chronic urticaria (AICU) except for the provocation test in vivo. To identify disease markers for AICU, we investigated the single nucleotide polymorphism (SNP) of the promoter loci of high-affinity IgE receptor (FcεRIα) and CD203c expression level in Chinese patients with AICU. We studied two genotypic and allelic frequencies of rs2427827 (–344C/T) and rs2251746 (–66T/C) gene polymorphisms of FcεRIα in 20 patients with AICU, 52 subjects with airway hypersensitivity without aspirin intolerance, and 50 controls in a Chinese population. The results showed that the frequencies of two SNPs (–344C>T, –66C>T) were similar to the normal controls. The allele frequency of –344CC was significantly higher in the patients with AICU compared to those with airway sensitivity (p = 0.019). We also studied both histamine release and CD203c expression on KU812 cells to assess aspirin-induced basophil activation. We found that the activity of basophil activation of AICU was significantly higher in the patients with AICU compared to those with airway hypersensitivity without aspirin intolerance. The mean fluorescence intensity of the CD203c expression were 122.5 ± 5.2 vs. 103.3 ± 3.3 respectively, (p < 0.05), and the percentages of histamine release were 31.3% ± 7.4% vs. −24.0% ± 17.5%, (p < 0.05) respectively. Although the mean fluorescence intensity of CD203c expression and the percentage of histamine release were significantly up-regulated by aspirin, they were not affected by anti-IgE antibodies. These results suggest that a single SNP of FcεRIα (–344C>T) is less likely to develop AICU and the basophil activation activity in the sera by measuring CD203c expression can be applicable to confirm the diagnosis of AICU. Full article

Open AccessArticle Joint Identification of Genetic Variants for Physical Activity in Korean Population

by Jayoun Kim, Jaehee Kim, Haesook Min, Sohee Oh, Yeonjung Kim, Andy H. Lee and Taesung Park

Int. J. Mol. Sci. 2014, 15(7), 12407-12421; doi:10.3390/ijms150712407

Received: 23 April 2014 / Accepted: 11 June 2014 / Published: 14 July 2014

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Abstract

There has been limited research on genome-wide association with physical activity (PA). This study ascertained genetic associations between PA and 344,893 single nucleotide polymorphism (SNP) markers in 8842 Korean samples. PA data were obtained from a validated questionnaire that included information on PA

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There has been limited research on genome-wide association with physical activity (PA). This study ascertained genetic associations between PA and 344,893 single nucleotide polymorphism (SNP) markers in 8842 Korean samples. PA data were obtained from a validated questionnaire that included information on PA intensity and duration. Metabolic equivalent of tasks were calculated to estimate the total daily PA level for each individual. In addition to single- and multiple-SNP association tests, a pathway enrichment analysis was performed to identify the biological significance of SNP markers. Although no significant SNP was found at genome-wide significance level via single-SNP association tests, 59 genetic variants mapped to 76 genes were identified via a multiple SNP approach using a bootstrap selection stability measure. Pathway analysis for these 59 variants showed that maturity onset diabetes of the young (MODY) was enriched. Joint identification of SNPs could enable the identification of multiple SNPs with good predictive power for PA and a pathway enriched for PA. Full article

Open AccessArticle Association of STAT3 Common Variations with Obesity and Hypertriglyceridemia: Protective and Contributive Effects

by Zuliang Ma, Guanghai Wang, Xuejiao Chen, Zejin Ou and Fei Zou

Int. J. Mol. Sci. 2014, 15(7), 12258-12269; doi:10.3390/ijms150712258

Received: 8 May 2014 / Revised: 9 June 2014 / Accepted: 19 June 2014 / Published: 10 July 2014

Cited by 1 | PDF Full-text (678 KB) | HTML Full-text | XML Full-text | Supplementary Files

Abstract

Signal transducer and activator of transcription 3 (STAT3) plays an important role in energy metabolism. Here we explore whether STAT3 common variations influence risks of obesity and other metabolic disorders in a Chinese Han population. Two tagging single nucleotide polymorphisms (tagSNPs), rs1053005 and

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Signal transducer and activator of transcription 3 (STAT3) plays an important role in energy metabolism. Here we explore whether STAT3 common variations influence risks of obesity and other metabolic disorders in a Chinese Han population. Two tagging single nucleotide polymorphisms (tagSNPs), rs1053005 and rs957970, were used to capture the common variations of STAT3. Relationships between genotypes and obesity, body mass index, plasma triglyceride and other metabolic diseases related parameters were analyzed for association study in 1742 subjects. Generalized linear model and logistic regression model were used for quantitative data analysis and case-control study, respectively. rs1053005 was significantly associated with body mass index and waist circumference (p = 0.013 and p = 0.02, respectively). rs957970 was significantly associated with plasma level of triglyceride (p = 0.007). GG genotype at rs1053005 had lower risks of both general obesity and central obesity (OR = 0.40, p = 0.034; OR = 0.42, p = 0.007, respectively) compared with AA genotype. CT genotype at rs957970 had a higher risk of hypertriglyceridemia (OR = 1.43, p = 0.015) compared with TT genotype. Neither of the two SNPs was associated with othermetabolic diseases related parameters. Our observations indicated that common variations of STAT3 could significantly affect the risk of obesity and hypertriglyceridemia in Chinese Han population. Full article

Open AccessArticle Weighted Risk Score-Based Multifactor Dimensionality Reduction to Detect Gene-Gene Interactions in Nasopharyngeal Carcinoma

by Chao-Feng Li, Fu-Tian Luo, Yi-Xin Zeng and Wei-Hua Jia

Int. J. Mol. Sci. 2014, 15(6), 10724-10737; doi:10.3390/ijms150610724

Received: 4 March 2014 / Revised: 21 April 2014 / Accepted: 3 June 2014 / Published: 13 June 2014

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Abstract

Determining the complex relationships between diseases, polymorphisms in human genes and environmental factors is challenging. Multifactor dimensionality reduction (MDR) has been proven to be capable of effectively detecting the statistical patterns of epistasis, although classification accuracy is required for this approach. The imbalanced

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Determining the complex relationships between diseases, polymorphisms in human genes and environmental factors is challenging. Multifactor dimensionality reduction (MDR) has been proven to be capable of effectively detecting the statistical patterns of epistasis, although classification accuracy is required for this approach. The imbalanced dataset can cause seriously negative effects on classification accuracy. Moreover, MDR methods cannot quantitatively assess the disease risk of genotype combinations. Hence, we introduce a novel weighted risk score-based multifactor dimensionality reduction (WRSMDR) method that uses the Bayesian posterior probability of polymorphism combinations as a new quantitative measure of disease risk. First, we compared the WRSMDR to the MDR method in simulated datasets. Our results showed that the WRSMDR method had reasonable power to identify high-order gene-gene interactions, and it was more effective than MDR at detecting four-locus models. Moreover, WRSMDR reveals more information regarding the effect of genotype combination on the disease risk, and the result was easier to determine and apply than with MDR. Finally, we applied WRSMDR to a nasopharyngeal carcinoma (NPC) case-control study and identified a statistically significant high-order interaction among three polymorphisms: rs2860580, rs11865086 and rs2305806. Full article

Open AccessReview Computational and Experimental Approaches to Reveal the Effects of Single Nucleotide Polymorphisms with Respect to Disease Diagnostics

by Tugba G. Kucukkal, Ye Yang, Susan C. Chapman, Weiguo Cao and Emil Alexov

Int. J. Mol. Sci. 2014, 15(6), 9670-9717; doi:10.3390/ijms15069670

Received: 8 April 2014 / Revised: 15 May 2014 / Accepted: 16 May 2014 / Published: 30 May 2014

Cited by 15 | PDF Full-text (1288 KB) | HTML Full-text | XML Full-text

Abstract

DNA mutations are the cause of many human diseases and they are the reason for natural differences among individuals by affecting the structure, function, interactions, and other properties of DNA and expressed proteins. The ability to predict whether a given mutation is disease-causing

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DNA mutations are the cause of many human diseases and they are the reason for natural differences among individuals by affecting the structure, function, interactions, and other properties of DNA and expressed proteins. The ability to predict whether a given mutation is disease-causing or harmless is of great importance for the early detection of patients with a high risk of developing a particular disease and would pave the way for personalized medicine and diagnostics. Here we review existing methods and techniques to study and predict the effects of DNA mutations from three different perspectives: in silico, in vitro and in vivo. It is emphasized that the problem is complicated and successful detection of a pathogenic mutation frequently requires a combination of several methods and a knowledge of the biological phenomena associated with the corresponding macromolecules. Full article

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Open AccessArticle Tagging SNPs in the MTHFR Gene and Risk of Ischemic Stroke in a Chinese Population

by Bao-Sheng Zhou, Guo-Yun Bu, Mu Li, Bin-Ge Chang and Yi-Pin Zhou

Int. J. Mol. Sci. 2014, 15(5), 8931-8940; doi:10.3390/ijms15058931

Received: 10 March 2014 / Revised: 7 May 2014 / Accepted: 8 May 2014 / Published: 20 May 2014

Cited by 13 | PDF Full-text (219 KB) | HTML Full-text | XML Full-text

Abstract

Stroke is currently the leading cause of functional impairments worldwide. Folate supplementation is inversely associated with risk of ischemic stroke. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism. The aim of this study is to examine whether genetic variants in

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Stroke is currently the leading cause of functional impairments worldwide. Folate supplementation is inversely associated with risk of ischemic stroke. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism. The aim of this study is to examine whether genetic variants in MTHFR gene are associated with the risk of ischemic stroke and fasting total serum homocysteine (tHcy) level. We genotyped nine tag SNPs in the MTHFR gene in a case-control study, including 543 ischemic stroke cases and 655 healthy controls in China. We found that subjects with the rs1801133 TT genotype and rs1801131 CC genotype had significant increased risks of ischemic stroke (adjusted odds ratio (OR) = 1.82, 95% confidence interval (CI): 1.27–2.61, p = 0.004; adjusted OR = 1.99, 95% CI: 1.12–3.56, p = 0.01) compared with subjects with the major alleles. Haplotype analysis also found that carriers of the MTHFR CTTCGA haplotype (rs12121543-rs13306553-rs9651118-rs1801133-rs2274976-rs1801131) had a significant reduced risk of ischemic stroke (adjusted OR = 0.53, 95% CI: 0.35–0.82) compared with those with the CTTTGA haplotype. Besides, the MTHFR rs1801133 and rs9651118 were significantly associated with serum levels of tHcy in healthy controls (p < 0.0001 and p = 0.02). These findings suggest that variants in the MTHFR gene may influence the risk of ischemic stroke and serum tHcy. Full article

Open AccessArticle Molecular Characterization of α- and β-Thalassaemia among Malay Patients

by Nur Fatihah Mohd Yatim, Masitah Abd. Rahim, Kavitha Menon, Faisal Muti Al-Hassan, Rahimah Ahmad, Anita Bhajan Manocha, Mohamed Saleem and Badrul Hisham Yahaya

Int. J. Mol. Sci. 2014, 15(5), 8835-8845; doi:10.3390/ijms15058835

Received: 11 February 2014 / Revised: 6 March 2014 / Accepted: 13 March 2014 / Published: 19 May 2014

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Abstract

Both α- and β-thalassaemia syndromes are public health problems in the multi-ethnic population of Malaysia. To molecularly characterise the α- and β-thalassaemia deletions and mutations among Malays from Penang, Gap-PCR and multiplexed amplification refractory mutation systems were used to study 13 α-thalassaemia determinants

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Both α- and β-thalassaemia syndromes are public health problems in the multi-ethnic population of Malaysia. To molecularly characterise the α- and β-thalassaemia deletions and mutations among Malays from Penang, Gap-PCR and multiplexed amplification refractory mutation systems were used to study 13 α-thalassaemia determinants and 20 β-thalassaemia mutations in 28 and 40 unrelated Malays, respectively. Four α-thalassaemia deletions and mutations were demonstrated. −−^SEA deletion and α^CSα accounted for more than 70% of the α-thalassaemia alleles. Out of the 20 β-thalassaemia alleles studied, nine different β-thalassaemia mutations were identified of which β^E accounted for more than 40%. We concluded that the highest prevalence of (α- and β-thalassaemia alleles in the Malays from Penang are −−^SEA deletion and β^E mutation, respectively. Full article

Open AccessArticle DEFLATE Compression Algorithm Corrects for Overestimation of Phylogenetic Diversity by Grantham Approach to Single-Nucleotide Polymorphism Classification

by Arran Schlosberg, Brian Y. H. Lam, Giles S. H. Yeo and Roderick J. Clifton-Bligh

Int. J. Mol. Sci. 2014, 15(5), 8491-8508; doi:10.3390/ijms15058491

Received: 22 January 2014 / Revised: 28 March 2014 / Accepted: 4 May 2014 / Published: 13 May 2014

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Abstract

Improvements in speed and cost of genome sequencing are resulting in increasing numbers of novel non-synonymous single nucleotide polymorphisms (nsSNPs) in genes known to be associated with disease. The large number of nsSNPs makes laboratory-based classification infeasible and familial co-segregation with disease is

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Improvements in speed and cost of genome sequencing are resulting in increasing numbers of novel non-synonymous single nucleotide polymorphisms (nsSNPs) in genes known to be associated with disease. The large number of nsSNPs makes laboratory-based classification infeasible and familial co-segregation with disease is not always possible. In-silico methods for classification or triage are thus utilised. A popular tool based on multiple-species sequence alignments (MSAs) and work by Grantham, Align-GVGD, has been shown to underestimate deleterious effects, particularly as sequence numbers increase. We utilised the DEFLATE compression algorithm to account for expected variation across a number of species. With the adjusted Grantham measure we derived a means of quantitatively clustering known neutral and deleterious nsSNPs from the same gene; this was then used to assign novel variants to the most appropriate cluster as a means of binary classification. Scaling of clusters allows for inter-gene comparison of variants through a single pathogenicity score. The approach improves upon the classification accuracy of Align-GVGD while correcting for sensitivity to large MSAs. Open-source code and a web server are made available at https://github.com/aschlosberg/CompressGV. Full article

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Open AccessArticle Different Role of Tumor Necrosis Factor-α Polymorphism in Non-Hodgkin Lymphomas among Caucasian and Asian Populations: A Meta-Analysis

by Kan Zhai, Jie Ding and Yan Zhou

Int. J. Mol. Sci. 2014, 15(5), 7684-7698; doi:10.3390/ijms15057684

Received: 12 March 2014 / Revised: 15 April 2014 / Accepted: 23 April 2014 / Published: 5 May 2014

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Abstract

Tumor necrosis factor-α (TNF-α) is an immunoregulatory cytokine involved in B- and T-cell function, and also plays an important role in inflammation and cancer. TNF-α-308G>A has been associated with constitutively elevated TNF-α expression. Several studies have reported the association between the TNF-α-308G>A polymorphism

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Tumor necrosis factor-α (TNF-α) is an immunoregulatory cytokine involved in B- and T-cell function, and also plays an important role in inflammation and cancer. TNF-α-308G>A has been associated with constitutively elevated TNF-α expression. Several studies have reported the association between the TNF-α-308G>A polymorphism and non-Hodgkin lymphomas (NHL) risk, however, results are still inconsistent. To solve these conflicts, we conducted the first meta-analysis to assess the effect of TNF-α-308G>A polymorphism on the risk of NHL and various subtypes (additive model) including 10,619 cases and 12,977 controls in Caucasian and Asian populations. Our meta-analysis indicated that TNF-α-308G>A polymorphism is not associated with NHL risk when pooling all studies together (OR = 1.06, 95% CI: 0.92–1.23, p = 0.413). In stratified analyses, we found TNF-α-308A allele was significantly associated with higher risk of NHL, B-cell lymphomas (BCL), T-cell lymphomas (TCL) and diffuse large B-cell lymphomas (DLBCL) in Caucasians (OR = 1.22, 95% CI: 1.06–1.40, p = 0.007; OR = 1.18, 95% CI: 1.03–1.34, p = 0.014; OR = 1.20, 95% CI: 1.01–1.42, p = 0.040; OR = 1.21, 95% CI: 1.11–1.32, p < 0.001, respectively). Interestingly, it was associated with decreased risk of NHL, BCL and DLBCL in Asians (OR = 0.75, 95% CI: 0.66–0.86, p < 0.001; OR = 0.70, 95% CI: 0.52–0.94, p = 0.018; OR = 0.70, 95% CI: 0.57–0.86, p = 0.001). These findings also suggest TNF-α might play a distinct role in pathogenesis of NHL in different populations. Full article

Open AccessArticle Development of a Multiplex and Cost-Effective Genotype Test toward More Personalized Medicine for the Antiplatelet Drug Clopidogrel

by Hye-Eun Jeong, Su-Jun Lee, Eun-Young Cha, Eun-Young Kim, Ho-Sook Kim, Young Hwan Song and Jae-Gook Shin

Int. J. Mol. Sci. 2014, 15(5), 7699-7710; doi:10.3390/ijms15057699

Received: 17 March 2014 / Revised: 20 April 2014 / Accepted: 22 April 2014 / Published: 5 May 2014

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Abstract

There has been a wide range of inter-individual variations in platelet responses to clopidogrel. The variations in response to clopidogrel can be driven by genetic polymorphisms involved in the pathway of absorption, distribution, metabolism, excretion, and the target receptor P2Y12. A set of

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There has been a wide range of inter-individual variations in platelet responses to clopidogrel. The variations in response to clopidogrel can be driven by genetic polymorphisms involved in the pathway of absorption, distribution, metabolism, excretion, and the target receptor P2Y12. A set of genetic variants known for causing variations in clopidogrel responses was selected, which included CYP2C19*2, *3, *17, CYP2B6*4, *6, *9, CYP3A4*18, CYP3A5*3, MDR1 2677G > T/A, 3435C > T, and P2Y12 H2 (742T > C). The simultaneous detection of these 10 variants was developed by using a multiplex PCR and single-base extension (MSSE) methodology. The newly developed genotyping test was confirmed by direct DNA sequencing in the representative positive control samples and validated in an extended set of 100 healthy Korean subjects. Genotyping results from the developed MSSE exhibited a perfect concordance with the direct DNA sequencing data and all of variants tested in 100 healthy Korean subjects were in agreement with Hardy-Weinberg equilibrium (p > 0.05). The present molecular diagnostic studies provide an accurate, convenient, and fast genotyping method for the detection of multiple variants. This would be helpful for researchers, as well as clinicians, to use genetic information toward more personalized medicine of clopidogrel and other antiplatelet drugs in the future. Full article

Open AccessArticle Polymorphisms in DNA Repair Genes (APEX1, XPD, XRCC1 and XRCC3) and Risk of Preeclampsia in a Mexican Mestizo Population

by Ada Sandoval-Carrillo, Edna M. Méndez-Hernández, Fernando Vazquez-Alaniz, Marisela Aguilar-Durán, Alfredo Téllez-Valencia, Marcelo Barraza-Salas, Francisco X. Castellanos-Juárez, Osmel La Llave-León and José M. Salas-Pacheco

Int. J. Mol. Sci. 2014, 15(3), 4273-4283; doi:10.3390/ijms15034273

Received: 21 January 2014 / Revised: 17 February 2014 / Accepted: 4 March 2014 / Published: 11 March 2014

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Abstract

Variations in genes involved in DNA repair systems have been proposed as risk factors for the development of preeclampsia (PE). We conducted a case-control study to investigate the association of Human apurinic/apyrimidinic (AP) endonuclease (APEX1) Asp148Glu (rs1130409), Xeroderma Pigmentosum group D

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Variations in genes involved in DNA repair systems have been proposed as risk factors for the development of preeclampsia (PE). We conducted a case-control study to investigate the association of Human apurinic/apyrimidinic (AP) endonuclease (APEX1) Asp148Glu (rs1130409), Xeroderma Pigmentosum group D (XPD) Lys751Gln (rs13181), X-ray repair cross-complementing group 1 (XRCC) Arg399Gln (rs25487) and X-ray repair cross-complementing group 3 (XRCC3) Thr241Met (rs861539) polymorphisms with PE in a Mexican population. Samples of 202 cases and 350 controls were genotyped using RTPCR. Association analyses based on a χ² test and binary logistic regression were performed to determine the odds ratio (OR) and a 95% confidence interval (95% CI) for each polymorphism. The allelic frequencies of APEX1 Asp148Glu polymorphism showed statistical significant differences between preeclamptic and normal women (p = 0.036). Although neither of the polymorphisms proved to be a risk factor for the disease, the APEX1 Asp148Glu polymorphism showed a tendency of association (OR: 1.74, 95% CI = 0.96–3.14) and a significant trend (p for trend = 0.048). A subgroup analyses revealed differences in the allelic frequencies of APEX1 Asp148Glu polymorphism between women with mild preeclampsia and severe preeclampsia (p = 0.035). In conclusion, our results reveal no association between XPD Lys751Gln, XRCC Arg399Gln and XRCC3 Thr241Met polymorphisms and the risk of PE in a Mexican mestizo population; however, the results in the APEX1 Asp148Glu polymorphism suggest the need for future studies using a larger sample size. Full article

Open AccessCommunication Novel Missense Mutation in the NOD2 Gene in a Patient with Early Onset Ulcerative Colitis: Causal or Chance Association?

by Martina Girardelli, Josef Vuch, Alberto Tommasini, Sergio Crovella and Anna Monica Bianco

Int. J. Mol. Sci. 2014, 15(3), 3834-3841; doi:10.3390/ijms15033834

Received: 7 January 2014 / Revised: 18 February 2014 / Accepted: 20 February 2014 / Published: 3 March 2014

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Abstract

Deregulated immune response to gut microflora in genetically predisposed individuals is typical for inflammatory bowel diseases. It is reasonable to assume that genetic association with the disease will be more pronounced in subjects with early onset than adult onset. The nucleotide-binding oligomerization domain

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Deregulated immune response to gut microflora in genetically predisposed individuals is typical for inflammatory bowel diseases. It is reasonable to assume that genetic association with the disease will be more pronounced in subjects with early onset than adult onset. The nucleotide-binding oligomerization domain containing-2 gene, commonly involved in multifactorial risk of Crohn’s disease, and interleukin 10 receptor genes, associated with rare forms of early onset inflammatory bowel diseases, were sequenced in an early onset patient. We identified a novel variant in the NOD2 gene (c.2857A > G p.K953E) and two already described missense variants in the IL10RA gene (S159G and G351R). The new NOD2 missense variant was examined in silico with two online bioinformatics tools to predict the potentially deleterious effects of the mutation. Although cumulative effect of these variations in the early onset of the disease can be only hypothesized, we demonstrated that family information and in silico studies can be used to predict association with the disease. Full article

Open AccessArticle Association between Single Nucleotide Polymorphism rs1044925 and the Risk of Coronary Artery Disease and Ischemic Stroke

by Dong-Feng Wu, Rui-Xing Yin, Xiao-Li Cao and Wu-Xian Chen

Int. J. Mol. Sci. 2014, 15(3), 3546-3559; doi:10.3390/ijms15033546

Received: 28 November 2013 / Revised: 30 January 2014 / Accepted: 13 February 2014 / Published: 26 February 2014

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Abstract

The present study was performed to clarify the association between the acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) single nucleotide polymorphism (SNP) rs1044925 and the risk of coronary artery disease (CAD) and ischemic stroke (IS) in the Guangxi Han population. Polymerase chain reaction and restriction

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The present study was performed to clarify the association between the acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) single nucleotide polymorphism (SNP) rs1044925 and the risk of coronary artery disease (CAD) and ischemic stroke (IS) in the Guangxi Han population. Polymerase chain reaction and restriction fragment length polymorphism was performed to determine the genotypes of the ACAT-1 SNP rs1044925 in 1730 unrelated subjects (CAD, 587; IS, 555; and healthy controls; 588). The genotypic and allelic frequencies of rs1044925 were significantly different between the CAD patients and controls (p = 0.015) and borderline different between the IS patients and controls (p = 0.05). The AC/CC genotypes and C allele were associated with a decreased risk of CAD and IS (CAD: p = 0.014 for AC/CC vs. AA, p = 0.022 for C vs. A; IS: p = 0.014 for AC/CC vs. AA; p = 0.017 for C vs. A). The AC/CC genotypes in the healthy controls, but not in CAD or IS patients, were associated with an increased serum high-density lipoprotein cholesterol (HDL-C) concentration. The present study shows that the C allele carriers of ACAT-1 rs1044925 were associated with an increased serum HDL-C level in the healthy controls and decreased risk in CAD and IS patients. Full article

Open AccessArticle E26 Transformation-Specific-1 (ETS1) and WDFY Family Member 4 (WDFY4) Polymorphisms in Chinese Patients with Rheumatoid Arthritis

by Yiqun Zhang, Lin Bo, Hui Zhang, Chao Zhuang and Ruiping Liu

Int. J. Mol. Sci. 2014, 15(2), 2712-2721; doi:10.3390/ijms15022712

Received: 5 January 2014 / Revised: 30 January 2014 / Accepted: 11 February 2014 / Published: 17 February 2014

Cited by 1 | PDF Full-text (192 KB) | HTML Full-text | XML Full-text | Supplementary Files

Abstract

E26 transformation-specific-1 (ETS1) and WDFY family member 4 (WDFY4) are closely related with systemic lupus erythematosus. We hypothesized that ETS1 and WDFY4 polymorphisms may contribute to rheumatoid arthritis (RA) susceptibility. We studied ETS1 rs1128334 G/A and WDFY4 rs7097397 A/G gene polymorphisms in 329

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E26 transformation-specific-1 (ETS1) and WDFY family member 4 (WDFY4) are closely related with systemic lupus erythematosus. We hypothesized that ETS1 and WDFY4 polymorphisms may contribute to rheumatoid arthritis (RA) susceptibility. We studied ETS1 rs1128334 G/A and WDFY4 rs7097397 A/G gene polymorphisms in 329 patients with RA and 697 controls in a Chinese population. Genotyping was done using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. When the WDFY4 rs7097397 AA homozygote genotype was used as the reference group, the AG genotype was associated with a significantly increased risk for RA. In the dominant model, when the WDFY4 rs7097397 AA homozygote genotype was used as the reference group, the AG/GG genotypes were associated with a significant increased susceptibility to RA. In stratification analyses, a significantly increased risk for RA associated with the WDFY4 rs7097397 AG genotype was evident among female patients, younger patients, C-reactive protein (CRP) negative patients and both anti-cyclic citrullinated peptide antibody (ACPA) positive patients and negative patients compared with the WDFY4 rs7097397 AA genotype. These findings suggested that WDFY4 rs7097397 A/G may be associated with the risk of RA, especially among younger, female patients, CRP-negative patients and both ACPA positive and negative patients. However, our results were obtained from a moderate-sized sample, and therefore this is a preliminary conclusion. To confirm these findings, validation by a larger study from a more diverse ethnic population is needed. Full article

Open AccessArticle Role of mtDNA Haplogroups in the Prevalence of Knee Osteoarthritis in a Southern Chinese Population

by Hezhi Fang, Xinwei Liu, Lijun Shen, Fengjie Li, Yihong Liu, Hongbo Chi, Huikai Miao, Jianxin Lu and Yidong Bai

Int. J. Mol. Sci. 2014, 15(2), 2646-2659; doi:10.3390/ijms15022646

Received: 1 January 2014 / Revised: 15 January 2014 / Accepted: 22 January 2014 / Published: 14 February 2014

Cited by 9 | PDF Full-text (341 KB) | HTML Full-text | XML Full-text

Abstract

Mitochondrial DNA (mtDNA) has been implicated in various human degenerative diseases. However, the role of mtDNA in Osteoarthritis (OA) is less known. To investigate whether mtDNA haplogroups contribute to the prevalence of knee OA, we have carried out a comprehensive case-control study on

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Mitochondrial DNA (mtDNA) has been implicated in various human degenerative diseases. However, the role of mtDNA in Osteoarthritis (OA) is less known. To investigate whether mtDNA haplogroups contribute to the prevalence of knee OA, we have carried out a comprehensive case-control study on 187 knee OA patients and 420 geographically matched controls in southern China. OA patients were classified on the Kellgren/Lawrence scale from two to four for the disease severity study and the data were analyzed by adjusting for age and sex. We found that patients with haplogroup G (OR = 3.834; 95% CI 1.139, 12.908; p = 0.03) and T16362C (OR = 1.715; 95% CI 1.174, 2.506; p = 0.005) exhibited an increased risk of OA occurrence. Furthermore, patients carrying haplogroup G had a higher severity progression of knee OA (OR = 10.870; 95% CI 1.307, 90.909; p = 0.007). On the other hand, people with haplogroup B/B4 (OR = 0.503; 95% CI 0.283, 0.893; p = 0.019)/(OR = 0.483; 95% CI 0.245, 0.954; p = 0.036) were less susceptible for OA occurrence. Interestingly, we found OA patients also exhibited a general increase in mtDNA content. Our study indicates that the mtDNA haplogroup plays a role in modulating OA development. Full article

Open AccessArticle The hOGG1 Ser326Cys Gene Polymorphism and the Risk of Coronary Ectasia in the Chinese Population

by Po-Chao Hsu, Chiao-Ling Wang, Ho-Ming Su, Suh-Hang Juo, Tsung-Hsien Lin, Wen-Chol Voon, Shyi-Jang Shin, Wen-Ter Lai and Sheng-Hsiung Sheu

Int. J. Mol. Sci. 2014, 15(1), 1671-1682; doi:10.3390/ijms15011671

Received: 14 November 2013 / Revised: 6 January 2014 / Accepted: 20 January 2014 / Published: 22 January 2014

Cited by 6 | PDF Full-text (314 KB) | HTML Full-text | XML Full-text

Abstract

Oxidative stress (OS) is related to vascular inflammation possibly, contributing to the development of coronary ectasia (CE). Base excision repair (BER) and nucleotide excision repair are the main DNA repair pathways that can help to remove 8-hydroxydeoxyguanine (8-OHdG), a marker of OS. Human

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Oxidative stress (OS) is related to vascular inflammation possibly, contributing to the development of coronary ectasia (CE). Base excision repair (BER) and nucleotide excision repair are the main DNA repair pathways that can help to remove 8-hydroxydeoxyguanine (8-OHdG), a marker of OS. Human 8-oxoguanine DNA glycosylase 1 (hOGG1) is a key enzyme of the BER pathway and catalyzes the removal of 8-OHdG. The aim of our study was to investigate the association between hOGG1 Ser326Cys gene polymorphism and CE in a Chinese population. Five-hundred forty-seven patients who underwent diagnostic coronary angiography in a tertiary medical center were recruited. The angiographic definition of CE is the diameter of the ectatic segment being more than 1.5 times larger compared with an adjacent healthy reference segment. The gene polymorphisms were analyzed by polymerase chain reaction. The urine 8OHdG concentration was measured using a commercial ELISA kit. The distribution of hOGG1 Ser326Cys genotypes was significantly different between CE and non-CE groups (p = 0.033). The odds ratio of CE development for the Ser to the Cys variant was 1.55 (95% confidence interval (CI), 1.04–2.31, p = 0.033). Both univariate and logistic regression analysis showed a significant association of hOGG1 Ser326Cys polymorphism in the dominant model with CE development (p = 0.009 and 0.011, respectively). Urine 8-OHdG levels were significantly higher in subjects carrying the hOGG1 Ser variant than in those with the Cys/Cys genotype (p < 0.03). In conclusion, our study suggests that the hOGG1 Ser326Cys gene variant might play a role in susceptibility to the development of CE. Full article

Open AccessArticle Analysis of the rs10046 Polymorphism of Aromatase (CYP19) in Premenopausal Onset of Human Breast Cancer

by Karin Zins, Maurice Mogg, Christian Schneeberger, Dietmar Abraham and Martin Schreiber

Int. J. Mol. Sci. 2014, 15(1), 712-724; doi:10.3390/ijms15010712

Received: 5 December 2013 / Revised: 23 December 2013 / Accepted: 25 December 2013 / Published: 7 January 2014

Cited by 13 | PDF Full-text (303 KB) | HTML Full-text | XML Full-text

Abstract

The CYP19 gene encodes aromatase, an enzyme catalyzing the conversion of androgens to estrogens. Studies analyzing associations between single nucleotide polymorphisms in CYP19 and breast cancer risk have shown inconsistent results. The rs10046 polymorphism is located in the 3' untranslated region of

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The CYP19 gene encodes aromatase, an enzyme catalyzing the conversion of androgens to estrogens. Studies analyzing associations between single nucleotide polymorphisms in CYP19 and breast cancer risk have shown inconsistent results. The rs10046 polymorphism is located in the 3' untranslated region of the CYP19 gene, but the influence of this polymorphism on breast cancer risk is unclear. In this study, we investigated the impact of rs10046 SNP on breast cancer risk, age at onset and association with clinical characteristics in an Austrian population of 274 breast cancer patients and 253 controls. The results show that a significantly increased fraction of patients with the TT genotype of rs10046 develop breast cancer under the age of 50 (41.8% of TT patients, compared to 26.6% of C carriers; p = 0.018, Chi-square test). No rs10046 genotypes were significantly associated with increased breast cancer risk or patient characteristics other than age at onset. These results suggest that the rs10046 polymorphism in the CYP19 gene may have an effect on breast cancer susceptibility at an age under 50 in the investigated population. Full article

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Open AccessArticle The Brachyury Gly177Asp SNP Is not Associated with a Risk of Skull Base Chordoma in the Chinese Population

by Zhen Wu, Ke Wang, Liang Wang, Jie Feng, Shuyu Hao, Kaibing Tian, Liwei Zhang, Guijun Jia, Hong Wan and Junting Zhang

Int. J. Mol. Sci. 2013, 14(11), 21258-21265; doi:10.3390/ijms141121258

Received: 27 May 2013 / Revised: 25 September 2013 / Accepted: 15 October 2013 / Published: 25 October 2013

Cited by 5 | PDF Full-text (205 KB) | HTML Full-text | XML Full-text

Abstract

A recent chordoma cancer genotyping study reveals that the rs2305089, a single nucleotide polymorphism (SNP) located in brachyury gene and a key gene in the development of notochord, is significantly associated with chordoma risk. The brachyury gene is believed to be one of

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A recent chordoma cancer genotyping study reveals that the rs2305089, a single nucleotide polymorphism (SNP) located in brachyury gene and a key gene in the development of notochord, is significantly associated with chordoma risk. The brachyury gene is believed to be one of the key genes involved in the pathogenesis of chordoma, a rare primary bone tumor originating along the spinal column or at the base of the skull. The association between the brachyury Gly177Asp single nucleotide polymorphism (SNP) and the risk of skull base chordoma in Chinese populations is currently unknown. We investigated the genotype distribution of this SNP in 65 skull-base chordoma cases and 120 healthy subjects. Comparisons of the genotype distributions and allele frequencies did not reveal any significant difference between the groups. Our data suggest that the brachyury Gly177Asp SNP is not involved in the risks of skull-base chordoma, at least in the Chinese population. Full article

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