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Genetic Variations in Human Diseases
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Genetic Variations in Human Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 15052

Special Issue Editor

Dr. Éva Kereszturi

E-Mail Website
Guest Editor
Institute of Biochemistry and Molecular Biology, Department of Molecular Biology, Semmelweis University, P.O. Box 2, H-1428 Budapest, Hungary
Interests: polymorphisms; mutation; molecular biology; functional assay; association study; lipid metabolism

Special Issue Information

Dear Colleagues, 

Over the past two decades, extensive efforts have been made to catalog human genetic variation and correlate it with phenotypic differences. Most common genetic variations have now been investigated in genome-wide studies and found to be statistically associated with many complex traits, including several important common diseases. Although these studies have provided new biological insights, only a limited amount of the heritable component of any complex trait has been identified, and it remains challenging to elucidate the functional link between associated variants and phenotypic characteristics. Further scientific and technological advances and a clear understanding of the molecular biological meaning of human genetic variability will be essential for future progress in the field. In this Special Issue, we collect original research articles and reviews that aim to examine and present the impact of human genetic variations on diseases in as many different aspects as possible. The focus of our interest is not limited to SNPs; length variations, CNVs, mutations, gene–environment interaction studies, and association and functional analyses in various complex or monogenic diseases (positive and negative results) are warmly welcome.

Dr. Éva Kereszturi
Guest Editor

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Keywords

  • polymorphism
  • mutation
  • length variation
  • functional analysis
  • association study
  • monogenic disorders
  • complex disorders

Published Papers (16 papers)

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15 pages, 1666 KiB  
Article
MicroRNA-Mediated Suppression of Glial Cell Line-Derived Neurotrophic Factor Expression Is Modulated by a Schizophrenia-Associated Non-Coding Polymorphism
by Gergely Keszler, Bálint Vékony, Zsuzsanna Elek, Zsófia Nemoda, Nóra Angyal, Zsófia Bánlaki, Réka Kovács-Nagy, Zsolt Rónai and János M. Réthelyi
Int. J. Mol. Sci. 2024, 25(8), 4477; https://doi.org/10.3390/ijms25084477 - 19 Apr 2024
Viewed by 425
Abstract
Plasma levels of glial cell line-derived neurotrophic factor (GDNF), a pivotal regulator of differentiation and survival of dopaminergic neurons, are reportedly decreased in schizophrenia. To explore the involvement of GDNF in the pathogenesis of the disease, a case–control association analysis was performed between [...] Read more.
Plasma levels of glial cell line-derived neurotrophic factor (GDNF), a pivotal regulator of differentiation and survival of dopaminergic neurons, are reportedly decreased in schizophrenia. To explore the involvement of GDNF in the pathogenesis of the disease, a case–control association analysis was performed between five non-coding single nucleotide polymorphisms (SNP) across the GDNF gene and schizophrenia. Of them, the ‘G’ allele of the rs11111 SNP located in the 3′ untranslated region (3′-UTR) of the gene was found to associate with schizophrenia. In silico analysis revealed that the rs11111 ‘G’ allele might create binding sites for three microRNA (miRNA) species. To explore the significance of this polymorphism, transient co-transfection assays were performed in human embryonic kidney 293T (HEK293T) cells with a luciferase reporter construct harboring either the ‘A’ or ‘G’ allele of the 3′-UTR of GDNF in combination with the hsa-miR-1185-1-3p pre-miRNA. It was demonstrated that in the presence of the rs11111 ‘G’ (but not the ‘A’) allele, hsa-miR-1185-2-3p repressed luciferase activity in a dose-dependent manner. Deletion of the miRNA binding site or its substitution with the complementary sequence abrogated the modulatory effect. Our results imply that the rs11111 ‘G’ allele occurring more frequently in patients with schizophrenia might downregulate GDNF expression in a miRNA-dependent fashion. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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19 pages, 5258 KiB  
Article
Convergent Mutations and Single Nucleotide Variants in Mitochondrial Genomes of Modern Humans and Neanderthals
by Renata C. Ferreira, Camila R. Rodrigues, James R. Broach and Marcelo R. S. Briones
Int. J. Mol. Sci. 2024, 25(7), 3785; https://doi.org/10.3390/ijms25073785 - 28 Mar 2024
Viewed by 581
Abstract
The genetic contributions of Neanderthals to the modern human genome have been evidenced by the comparison of present-day human genomes with paleogenomes. Neanderthal signatures in extant human genomes are attributed to intercrosses between Neanderthals and archaic anatomically modern humans (AMHs). Although Neanderthal signatures [...] Read more.
The genetic contributions of Neanderthals to the modern human genome have been evidenced by the comparison of present-day human genomes with paleogenomes. Neanderthal signatures in extant human genomes are attributed to intercrosses between Neanderthals and archaic anatomically modern humans (AMHs). Although Neanderthal signatures are well documented in the nuclear genome, it has been proposed that there is no contribution of Neanderthal mitochondrial DNA to contemporary human genomes. Here we show that modern human mitochondrial genomes contain 66 potential Neanderthal signatures, or Neanderthal single nucleotide variants (N-SNVs), of which 36 lie in coding regions and 7 result in nonsynonymous changes. Seven N-SNVs are associated with traits such as cycling vomiting syndrome, Alzheimer’s disease and Parkinson’s disease, and two N-SNVs are associated with intelligence quotient. Based on recombination tests, principal component analysis (PCA) and the complete absence of these N-SNVs in 41 archaic AMH mitogenomes, we conclude that convergent evolution, and not recombination, explains the presence of N-SNVs in present-day human mitogenomes. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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15 pages, 5060 KiB  
Article
KCNQ1 p.D446E Variant as a Risk Allele for Arrhythmogenic Phenotypes: Electrophysiological Characterization Reveals a Complex Phenotype Affecting the Slow Delayed Rectifier Potassium Current (IKs) Voltage Dependence by Causing a Hyperpolarizing Shift and a Lack of Response to Protein Kinase A Activation
by Antonia González-Garrido, Omar López-Ramírez, Abel Cerda-Mireles, Thania Navarrete-Miranda, Aranza Iztanami Flores-Arenas, Arturo Rojo-Domínguez, Leticia Arregui, Pedro Iturralde, Erika Antúnez-Argüelles, Mayra Domínguez-Pérez, Leonor Jacobo-Albavera, Alessandra Carnevale and Teresa Villarreal-Molina
Int. J. Mol. Sci. 2024, 25(2), 953; https://doi.org/10.3390/ijms25020953 - 12 Jan 2024
Viewed by 729
Abstract
Genetic testing is crucial in inherited arrhythmogenic channelopathies; however, the clinical interpretation of genetic variants remains challenging. Incomplete penetrance, oligogenic, polygenic or multifactorial forms of channelopathies further complicate variant interpretation. We identified the KCNQ1/p.D446E variant in 2/63 patients with long QT syndrome, [...] Read more.
Genetic testing is crucial in inherited arrhythmogenic channelopathies; however, the clinical interpretation of genetic variants remains challenging. Incomplete penetrance, oligogenic, polygenic or multifactorial forms of channelopathies further complicate variant interpretation. We identified the KCNQ1/p.D446E variant in 2/63 patients with long QT syndrome, 30-fold more frequent than in public databases. We thus characterized the biophysical phenotypes of wildtype and mutant IKs co-expressing these alleles with the β-subunit minK in HEK293 cells. KCNQ1 p.446E homozygosity significantly shifted IKs voltage dependence to hyperpolarizing potentials in basal conditions (gain of function) but failed to shift voltage dependence to hyperpolarizing potentials (loss of function) in the presence of 8Br-cAMP, a protein kinase A activator. Basal IKs activation kinetics did not differ among genotypes, but in response to 8Br-cAMP, IKs 446 E/E (homozygous) activation kinetics were slower at the most positive potentials. Protein modeling predicted a slower transition of the 446E Kv7.1 tetrameric channel to the stabilized open state. In conclusion, biophysical and modelling evidence shows that the KCNQ1 p.D446E variant has complex functional consequences including both gain and loss of function, suggesting a contribution to the pathogenesis of arrhythmogenic phenotypes as a functional risk allele. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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10 pages, 1056 KiB  
Article
Single-Nucleotide Polymorphisms of the PAR2 and IL-17A Genes Are Significantly Associated with Chronic Pain
by Moe Soeda, Seii Ohka, Daisuke Nishizawa, Masako Iseki, Keisuke Yamaguchi, Hideko Arita, Kazuo Hanaoka, Jitsu Kato, Setsuro Ogawa, Ayako Hiranuma, Junko Hasegawa, Kyoko Nakayama, Yuko Ebata, Masakazu Hayashida, Tatsuya Ichinohe, Ken-ichi Fukuda and Kazutaka Ikeda
Int. J. Mol. Sci. 2023, 24(24), 17627; https://doi.org/10.3390/ijms242417627 - 18 Dec 2023
Viewed by 728
Abstract
Patients with chronic pain are affected psychologically and socially. There are also individual differences in treatment efficacy. Insufficient research has been conducted on genetic polymorphisms that are related to individual differences in the susceptibility to chronic pain. Autoimmune disorders can lead to inflammation [...] Read more.
Patients with chronic pain are affected psychologically and socially. There are also individual differences in treatment efficacy. Insufficient research has been conducted on genetic polymorphisms that are related to individual differences in the susceptibility to chronic pain. Autoimmune disorders can lead to inflammation and chronic pain; therefore, we focused on the autoimmune-related protease-activated receptor 2 (PAR2/F2RL1) and interleukin 17A (IL-17A/IL17A) genes. PAR2 and IL-17A are associated with autoimmune diseases that lead to chronic pain, and PAR2 regulates T-helper (Th) cell activation and differentiation. We hypothesized that the PAR2 and IL-17A genes are associated with chronic pain. The present study used a case–control design to statistically examine associations between genetic polymorphisms and the vulnerability to chronic pain. The rs2243057 polymorphism of the PAR2 gene and rs3819025 polymorphism of the IL-17A gene were previously reported to be associated with pain- or autoimmune-related phenotypes. Thus, these polymorphisms were investigated in the present study. We found that both rs2243057 and rs3819025 were significantly associated with a susceptibility to chronic pain. The present findings revealed autoimmune-related genetic factors that are involved in individual differences in chronic pain, further aiding understanding of the pathomechanism that underlies chronic pain and possibly contributing to future personalized medicine. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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10 pages, 577 KiB  
Article
Predicting the Impact of OTOF Gene Missense Variants on Auditory Neuropathy Spectrum Disorder
by Dmitry A. Dmitriev, Boris V. Shilov, Michail M. Polunin, Anton D. Zadorozhny and Alexey A. Lagunin
Int. J. Mol. Sci. 2023, 24(24), 17240; https://doi.org/10.3390/ijms242417240 - 07 Dec 2023
Viewed by 914
Abstract
Auditory neuropathy spectrum disorder (ANSD) associated with mutations of the OTOF gene is one of the common types of sensorineural hearing loss of a hereditary nature. Due to its high genetic heterogeneity, ANSD is considered one of the most difficult hearing disorders to [...] Read more.
Auditory neuropathy spectrum disorder (ANSD) associated with mutations of the OTOF gene is one of the common types of sensorineural hearing loss of a hereditary nature. Due to its high genetic heterogeneity, ANSD is considered one of the most difficult hearing disorders to diagnose. The dataset from 270 known annotated single amino acid substitutions (SAV) related to ANSD was created. It was used to estimate the accuracy of pathogenicity prediction using the known (from dbNSFP4.4) method and a new one. The new method (ConStruct) for the creation of the protein-centric classification model is based on the use of Random Forest for the analysis of missense variants in exons of the OTOF gene. A system of predictor variables was developed based on the modern understanding of the structure and function of the otoferlin protein and reflecting the location of changes in the tertiary structure of the protein due to mutations in the OTOF gene. The conservation values of nucleotide substitutions in genomes of 100 vertebrates and 30 primates were also used as variables. The average prediction of balanced accuracy and the AUC value calculated by the 5-fold cross-validation procedure were 0.866 and 0.903, respectively. The model shows good results for interpreting data from the targeted sequencing of the OTOF gene and can be implemented as an auxiliary tool for the diagnosis of ANSD in the early stages of ontogenesis. The created model, together with the results of the pathogenicity prediction of SAVs via other known accurate methods, were used for the evaluation of a manually created set of 1302 VUS related to ANSD. Based on the analysis of predicted results, 16 SAVs were selected as the new most probable pathogenic variants. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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12 pages, 2068 KiB  
Article
Exploring the Contribution of the Transporter AGT1/rBAT in Cystinuria Progression: Insights from Mouse Models and a Retrospective Cohort Study
by Clara Mayayo-Vallverdú, Esther Prat, Marta Vecino-Pérez, Laura González, Silvia Gràcia-Garcia, Luz San Miguel, Noelia Lopera, Angela Arias, Rafael Artuch, Miguel López de Heredia, Carlos Torrecilla, Ferran Rousaud-Barón, Oriol Angerri, Ekaitz Errasti-Murugarren and Virginia Nunes
Int. J. Mol. Sci. 2023, 24(24), 17140; https://doi.org/10.3390/ijms242417140 - 05 Dec 2023
Viewed by 729
Abstract
More than 20 years have passed since the identification of SLC3A1 and SLC7A9 as causative genes for cystinuria. However, cystinuria patients exhibit significant variability in the age of lithiasis onset, recurrence, and response to treatment, suggesting the presence of modulatory factors influencing cystinuria [...] Read more.
More than 20 years have passed since the identification of SLC3A1 and SLC7A9 as causative genes for cystinuria. However, cystinuria patients exhibit significant variability in the age of lithiasis onset, recurrence, and response to treatment, suggesting the presence of modulatory factors influencing cystinuria severity. In 2016, a second renal cystine transporter, AGT1, encoded by the SLC7A13 gene, was discovered. Although it was discarded as a causative gene for cystinuria, its possible effect as a modulatory gene remains unexplored. Thus, we analyzed its function in mouse models of cystinuria, screened the SLC7A13 gene in 34 patients with different lithiasic phenotypes, and functionally characterized the identified variants. Mice results showed that AGT1/rBAT may have a protective role against cystine lithiasis. In addition, among the four missense variants detected in patients, two exhibited a 25% impairment in AGT1/rBAT transport. However, no correlation between SLC7A13 genotypes and lithiasis phenotypes was observed in patients, probably because these variants were found in heterozygous states. In conclusion, our results, consistent with a previous study, suggest that AGT1/rBAT does not have a relevant effect on cystinuria patients, although an impact in patients carrying homozygous pathogenic variants cannot be discarded. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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16 pages, 583 KiB  
Article
Genetic Correlation of miRNA Polymorphisms and STAT3 Signaling Pathway with Recurrent Implantation Failure in the Korean Population
by Jung Hun Lee, Eun Hee Ahn, Min Jung Kwon, Chang Su Ryu, Yong Hyun Ha, Eun Ju Ko, Jeong Yong Lee, Ji Young Hwang, Ji Hyang Kim, Young Ran Kim and Nam Keun Kim
Int. J. Mol. Sci. 2023, 24(23), 16794; https://doi.org/10.3390/ijms242316794 - 27 Nov 2023
Cited by 1 | Viewed by 774
Abstract
The growing prevalence of in vitro fertilization-embryo transfer procedures has resulted in an increased incidence of recurrent implantation failure (RIF), necessitating focused research in this area. STAT3, a key factor in maternal endometrial remodeling and stromal proliferation, is crucial for successful embryo implantation. [...] Read more.
The growing prevalence of in vitro fertilization-embryo transfer procedures has resulted in an increased incidence of recurrent implantation failure (RIF), necessitating focused research in this area. STAT3, a key factor in maternal endometrial remodeling and stromal proliferation, is crucial for successful embryo implantation. While the relationship between STAT3 and RIF has been studied, the impact of single nucleotide polymorphisms (SNPs) in miRNAs, well-characterized gene expression modulators, on STAT3 in RIF cases remains uncharacterized. Here, we investigated 161 RIF patients and 268 healthy control subjects in the Korean population, analyzing the statistical association between miRNA genetic variants and RIF risk. We aimed to determine whether SNPs in specific miRNAs, namely miR-218-2 rs11134527 G>A, miR-34a rs2666433 G>A, miR-34a rs6577555 C>A, and miR-130a rs731384 G>A, were significantly associated with RIF risk. We identified a significant association between miR-34a rs6577555 C>A and RIF prevalence (implantation failure [IF] ≥ 2: adjusted odds ratio [AOR] = 2.264, 95% CI = 1.007–5.092, p = 0.048). These findings suggest that miR-34a rs6577555 C>A may contribute to an increased susceptibility to RIF. However, further investigations are necessary to elucidate the precise mechanisms underlying the role of miR-34a rs6577555 C>A in RIF. This study sheds light on the genetic and molecular factors underlying RIF, offering new avenues for research and potential advancements in the diagnosis and treatment of this complex condition. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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13 pages, 2534 KiB  
Article
Hearing and Hearing Loss Progression in Patients with GJB2 Gene Mutations: A Long-Term Follow-Up
by Aki Sakata, Akinori Kashio, Misaki Koyama, Shinji Urata, Hajime Koyama and Tatsuya Yamasoba
Int. J. Mol. Sci. 2023, 24(23), 16763; https://doi.org/10.3390/ijms242316763 - 25 Nov 2023
Cited by 1 | Viewed by 951
Abstract
We aimed to investigate whether the degree of hearing loss with GJB2 mutations could be predicted by distinguishing between truncating and non-truncating mutations and whether the genotype could predict the hearing loss level. Additionally, we examined the progression of hearing loss in individuals [...] Read more.
We aimed to investigate whether the degree of hearing loss with GJB2 mutations could be predicted by distinguishing between truncating and non-truncating mutations and whether the genotype could predict the hearing loss level. Additionally, we examined the progression of hearing loss in individuals monitored for over 2 years for an average of 6.9 years. The proportion of truncating mutations was higher in patients with profound and severe hearing loss, but it was not accurate enough to predict the degree of hearing loss. Via genotype analysis, mutations of the p.Arg143Trp variants were associated with profound hearing loss, while mutations of the p.Leu79Cysfs*3 allele exhibited a wide range of hearing loss, suggesting that specific genotypes can predict the hearing loss level. Notably, there were only three cases of progression in four ears, all of which involved the p.Leu79Cysfs*3 mutation. Over the long-term follow-up, 4000 Hz was significant, and there was a trend of progression at 250 Hz, suggesting that close monitoring at these frequencies during follow-up may be crucial to confirm progression. The progression of hearing loss was observed in moderate or severe hearing loss cases at the time of the initial diagnosis, emphasizing that children with this level of hearing loss need regular follow-ups. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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16 pages, 5266 KiB  
Article
Structural Variation Evolution at the 15q11-q13 Disease-Associated Locus
by Annalisa Paparella, Alberto L’Abbate, Donato Palmisano, Gerardina Chirico, David Porubsky, Claudia R. Catacchio, Mario Ventura, Evan E. Eichler, Flavia A. M. Maggiolini and Francesca Antonacci
Int. J. Mol. Sci. 2023, 24(21), 15818; https://doi.org/10.3390/ijms242115818 - 31 Oct 2023
Viewed by 926
Abstract
The impact of segmental duplications on human evolution and disease is only just starting to unfold, thanks to advancements in sequencing technologies that allow for their discovery and precise genotyping. The 15q11-q13 locus is a hotspot of recurrent copy number variation associated with [...] Read more.
The impact of segmental duplications on human evolution and disease is only just starting to unfold, thanks to advancements in sequencing technologies that allow for their discovery and precise genotyping. The 15q11-q13 locus is a hotspot of recurrent copy number variation associated with Prader–Willi/Angelman syndromes, developmental delay, autism, and epilepsy and is mediated by complex segmental duplications, many of which arose recently during evolution. To gain insight into the instability of this region, we characterized its architecture in human and nonhuman primates, reconstructing the evolutionary history of five different inversions that rearranged the region in different species primarily by accumulation of segmental duplications. Comparative analysis of human and nonhuman primate duplication structures suggests a human-specific gain of directly oriented duplications in the regions flanking the GOLGA cores and HERC segmental duplications, representing potential genomic drivers for the human-specific expansions. The increasing complexity of segmental duplication organization over the course of evolution underlies its association with human susceptibility to recurrent disease-associated rearrangements. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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15 pages, 743 KiB  
Article
Comprehensive Analysis of the Role of Gene Variants in Matrix Metalloproteinases and Their Tissue Inhibitors in Retinopathy of Prematurity: A Study in the Polish Population
by Aneta Choręziak-Michalak, Dawid Szpecht, Anna Chmielarz-Czarnocińska, Agnieszka Seremak-Mrozikiewicz, Krzysztof Drews, Grażyna Kurzawińska, Ewa Strauss and Anna Gotz-Więckowska
Int. J. Mol. Sci. 2023, 24(20), 15309; https://doi.org/10.3390/ijms242015309 - 18 Oct 2023
Viewed by 764
Abstract
This study was designed to investigate the relationship between variants of matrix metalloproteinases (MMP-1 rs179975, MMP-9 rs17576 and rs17577), their tissue inhibitors (TIMP-1 rs4898, TIMP-2 rs2277698 and rs55743137) and the development of retinopathy of prematurity (ROP) in [...] Read more.
This study was designed to investigate the relationship between variants of matrix metalloproteinases (MMP-1 rs179975, MMP-9 rs17576 and rs17577), their tissue inhibitors (TIMP-1 rs4898, TIMP-2 rs2277698 and rs55743137) and the development of retinopathy of prematurity (ROP) in infants from the Polish population. A cohort of 100 premature infants (47% female) was enrolled, including 50 ROP cases and 50 no-ROP controls. Patients with ROP were divided into those with spontaneous remission and those requiring treatment. A positive association between MMP-1 rs179975 1G deletion allele and ROP was observed in the log-additive model (OR = 5.01; p = 0.048). Furthermore, female neonates were observed to have a negative association between the TIMP-1 rs4898C allele and the occurrence of ROP and ROP requiring treatment (codominant models with respective p-values < 0.05 and 0.043). Two and three loci interactions between MMP-1 rs1799750 and TIMP1rs4989 (p = 0.015), as well as MMP-1 rs1799750, MMP-9 rs17576 and TIMP-1 rs4989 (p = 0.0003) variants influencing the ROP risk were also observed. In conclusion, these findings suggest a potential role of MMPs and TIMPs genetic variations in the development of ROP in the Polish population. Further studies using a larger group of premature infants will be required for validation. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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16 pages, 3650 KiB  
Article
Contribution of ADD3 and the HLA Genes to Biliary Atresia Risk in Chinese
by Meng-Meng Cui, Yi-Ming Gong, Wei-Hua Pan, Hao-Yue Pei, Mei-Rong Bai, Huan-Lei Song, Xin-Ru Han, Wen-Jie Wu, Wen-Wen Yu, Bei-Lin Gu, Wei Cai, Ying Zhou and Xun Chu
Int. J. Mol. Sci. 2023, 24(19), 14719; https://doi.org/10.3390/ijms241914719 - 29 Sep 2023
Viewed by 1012
Abstract
Nonsyndromic biliary atresia (BA) is a rare polygenic disease, with autoimmunity, virus infection and inflammation thought to play roles in its pathogenesis. We conducted a genome-wide association study in 336 nonsyndromic BA infants and 8900 controls. Our results validated the association of rs17095355 [...] Read more.
Nonsyndromic biliary atresia (BA) is a rare polygenic disease, with autoimmunity, virus infection and inflammation thought to play roles in its pathogenesis. We conducted a genome-wide association study in 336 nonsyndromic BA infants and 8900 controls. Our results validated the association of rs17095355 in ADD3 with BA risk (odds ratio (OR) = 1.70, 95% confidence interval (95% CI) = 1.49–1.99; p = 4.07 × 10−11). An eQTL analysis revealed that the risk allele of rs17095355 was associated with increased expression of ADD3. Single-cell RNA-sequencing data and immunofluorescence analysis revealed that ADD3 was moderately expressed in cholangiocytes and weakly expressed in hepatocytes. Immuno-fluorescent staining showed abnormal deposition of ADD3 in the cytoplasm of BA hepatocytes. No ADD3 auto-antibody was observed in the plasma of BA infants. In the HLA gene region, no variants achieved genome-wide significance. HLA-DQB1 residue Ala57 is the most significant residue in the MHC region (OR = 1.44, 95% CI = 1.20–1.74; p = 1.23 × 10−4), and HLA-DQB1 was aberrantly expressed in the bile duct cells. GWAS stratified by cytomegalovirus (CMV) IgM status in 87 CMV IgM (+) BA cases versus 141 CMV IgM (−) BA cases did not yield genome-wide significant associations. These findings support the notion that common variants of ADD3 account for BA risk. The HLA genes might have a minimal role in the genetic predisposition of BA due to the weak association signal. CMV IgM (+) BA patients might not have different genetic risk factor profiles compared to CMV IgM (−) subtype. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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16 pages, 1191 KiB  
Article
Potential Association of Cytochrome P450 Copy Number Alteration in Tumour with Chemotherapy Resistance in Lung Adenocarcinoma Patients
by Evelyn Incze, Katalin Mangó, Ferenc Fekete, Ádám Ferenc Kiss, Ádám Póti, Tünde Harkó, Judit Moldvay, Dávid Szüts and Katalin Monostory
Int. J. Mol. Sci. 2023, 24(17), 13380; https://doi.org/10.3390/ijms241713380 - 29 Aug 2023
Cited by 1 | Viewed by 1014
Abstract
Resistance to anticancer agents is a major obstacle to efficacious tumour therapy and responsible for high cancer-related mortality rates. Some resistance mechanisms are associated with pharmacokinetic variability in anticancer drug exposure due to genetic polymorphisms of drug-metabolizing cytochrome P450 (CYP) enzymes, whereas variations [...] Read more.
Resistance to anticancer agents is a major obstacle to efficacious tumour therapy and responsible for high cancer-related mortality rates. Some resistance mechanisms are associated with pharmacokinetic variability in anticancer drug exposure due to genetic polymorphisms of drug-metabolizing cytochrome P450 (CYP) enzymes, whereas variations in tumoural metabolism as a consequence of CYP copy number alterations are assumed to contribute to the selection of resistant cells. A high-throughput quantitative polymerase chain reaction (qPCR)-based method was developed for detection of CYP copy number alterations in tumours, and a scoring system improved the identification of inappropriate reference genes that underwent deletion/multiplication in tumours. The copy numbers of both the target (CYP2C8, CYP3A4) and the reference genes (ALB, B2M, BCKDHA, F5, CD36, MPO, TBP, RPPH1) established in primary lung adenocarcinoma by the qPCR-based method were congruent with those determined by next-generation sequencing (for 10 genes, slope = 0.9498, r2 = 0.72). In treatment naïve adenocarcinoma samples, the copy number multiplication of paclitaxel-metabolizing CYP2C8 and/or CYP3A4 was more prevalent in non-responder patients with progressive disease/exit than in responders with complete remission. The high-throughput qPCR-based method can become an alternative approach to next-generation sequencing in routine clinical practice, and identification of altered CYP copy numbers may provide a promising biomarker for therapy-resistant tumours. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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12 pages, 613 KiB  
Article
Genetic Variation in miR-27a Is Associated with Fluoropyrimidine-Associated Toxicity in Patients with Dihydropyrimidine Dehydrogenase Variants after Genotype-Guided Dose Reduction
by Samantha Medwid, Theodore J. Wigle, Cameron Ross and Richard B. Kim
Int. J. Mol. Sci. 2023, 24(17), 13284; https://doi.org/10.3390/ijms241713284 - 27 Aug 2023
Cited by 1 | Viewed by 837
Abstract
Dihydropyrimidine dehydrogenase (DPYD) is the rate-limiting enzyme involved in the metabolism of fluoropyrimidine-based chemotherapy. However, single-nucleotide variants (SNVs) in DPYD only partially explain fluoropyrimidine-induced toxicity. The expression of DPYD has previously been shown to be regulated by microRNA-27a (miR-27a) and a [...] Read more.
Dihydropyrimidine dehydrogenase (DPYD) is the rate-limiting enzyme involved in the metabolism of fluoropyrimidine-based chemotherapy. However, single-nucleotide variants (SNVs) in DPYD only partially explain fluoropyrimidine-induced toxicity. The expression of DPYD has previously been shown to be regulated by microRNA-27a (miR-27a) and a common miR-27a SNV (rs895819) has been associated with an increased risk of toxicity in patients harboring a DPYD variant who received standard fluoropyrimidine dosing. We investigated if the miR-27a rs895819 SNV was associated with toxicity in DPYD wildtype patients and carriers of DPYD variants who received a reduced dose. The regulation of DPYD using miR-27a was investigated in HepG2 cells utilizing a miR-27a mimic. miR-27a overexpression decreased DPYD mRNA expression compared to control cells (p < 0.0001). In a cohort of patients that received pre-emptive DPYD genotyping, 45 patients had a DPYD variant and 180 were wildtype. Patients heterozygous for rs895819 had an increased risk of toxicity, which was seen in both patients who were wildtype for DPYD variants (OR (95%CI) = 1.99 (1.00–3.99)) and DPYD variant carriers (OR (95%CI) = 8.10 (1.16–86.21)). Therefore, miR-27a rs895819 may be a clinically relevant predictor of fluoropyrimidine-associated toxicities. Furthermore, toxicity was more profound in DPYD variant carriers, even after DPYD genotype-guided dose reduction. This suggests that patients may benefit from miR-27a genotyping to guide fluoropyrimidine dosing. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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12 pages, 293 KiB  
Article
Chronic Kidney Disease: Interaction of Adiponectin Gene Polymorphisms and Diabetes
by Hsi-Hsien Chen, Ya-Li Huang, Mei-Chieh Chen, Chih-Yin Wu, Ying-Chin Lin, Horng-Sheng Shiue, Sheng-Lun Hsu and Yu-Mei Hsueh
Int. J. Mol. Sci. 2023, 24(9), 8128; https://doi.org/10.3390/ijms24098128 - 01 May 2023
Cited by 2 | Viewed by 1407
Abstract
Adiponectin is an adipokine multipeptide hormone with insulin-sensitizing; anti-atherosclerotic; and anti-inflammatory properties. Chronic kidney disease (CKD) may be associated with low adiponectin. The adiponectin gene ADIPOQ is thought to be the only major gene responsible for plasma adiponectin levels; which are associated with [...] Read more.
Adiponectin is an adipokine multipeptide hormone with insulin-sensitizing; anti-atherosclerotic; and anti-inflammatory properties. Chronic kidney disease (CKD) may be associated with low adiponectin. The adiponectin gene ADIPOQ is thought to be the only major gene responsible for plasma adiponectin levels; which are associated with diabetes and diabetic nephropathy. The purpose of this study was to investigate the association between ADIPOQ polymorphism and CKD. In addition; the combined effects of ADIPOQ polymorphism and diabetes and levels of total urinary arsenic and blood cadmium on CKD were also explored. This study included 215 CKD patients and 423 age–sex matched controls. The ADIPOQ polymorphisms were determined using the Agena Bioscience Mass ARRAY System. The levels of blood cadmium and urinary arsenic species were measured. The ADIPOQ rs182052 GA/AA genotype had a marginally lower odds ratio (OR) for CKD than the GG genotype. The OR (95% confidence interval; CI) was 16.33 (5.72–46.66) of CKD in subjects carrying the ADIPOQ rs182052 GG genotype and diabetes compared to non-diabetes subjects carrying the ADIPOQ rs182052 GA/AA genotype; the interaction term had p = 0.015; and the synergy index was 6.64 (1.81–24.36) after multivariate adjustment. A significant interaction of diabetes and ADIPOQ rs1501299 risk genotype increased the OR of CKD after multivariate adjustment with a synergy index of 0.31 (0.11–0.86) and a multiplicative interaction with p = 0.001. These results suggest that ADIPOQ rs182052 and rs1501299 risk genotypes may significantly modify the association between diabetes and CKD but not the association between total urinary arsenic and blood cadmium and CKD. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)

Review

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20 pages, 952 KiB  
Review
Diversity and Classification of Genetic Variations in Autism Spectrum Disorder
by Éva Kereszturi
Int. J. Mol. Sci. 2023, 24(23), 16768; https://doi.org/10.3390/ijms242316768 - 26 Nov 2023
Cited by 2 | Viewed by 1494
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition with symptoms that affect the whole personality and all aspects of life. Although there is a high degree of heterogeneity in both its etiology and its characteristic behavioral patterns, the disorder is well-captured along the [...] Read more.
Autism spectrum disorder (ASD) is a neurodevelopmental condition with symptoms that affect the whole personality and all aspects of life. Although there is a high degree of heterogeneity in both its etiology and its characteristic behavioral patterns, the disorder is well-captured along the autistic triad. Currently, ASD status can be confirmed following an assessment of behavioral features, but there is a growing emphasis on conceptualizing autism as a spectrum, which allows for establishing a diagnosis based on the level of support need, free of discrete categories. Since ASD has a high genetic predominance, the number of genetic variations identified in the background of the condition is increasing exponentially as genetic testing methods are rapidly evolving. However, due to the huge amount of data to be analyzed, grouping the different DNA variations is still challenging. Therefore, in the present review, a multidimensional classification scheme was developed to accommodate most of the currently known genetic variants associated with autism. Genetic variations have been grouped according to six criteria (extent, time of onset, information content, frequency, number of genes involved, inheritance pattern), which are themselves not discrete categories, but form a coherent continuum in line with the autism spectrum approach. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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Other

Jump to: Research, Review

9 pages, 259 KiB  
Brief Report
Association of HLA-A*11:01, -A*24:02, and -B*18:01 with Prostate Cancer Risk: A Case-Control Study
by Maria Antonietta Manca, Elena Rita Simula, Davide Cossu, Tatiana Solinas, Massimo Madonia, Roberto Cusano and Leonardo Antonio Sechi
Int. J. Mol. Sci. 2023, 24(20), 15398; https://doi.org/10.3390/ijms242015398 - 20 Oct 2023
Viewed by 812
Abstract
The major histocompatibility complex (MHC) loci, the most polymorphic regions within the human genome, encode protein complexes responsible for antigen presentation and CD4+ and CD8+ cell activation. In prostate cancer (PCa), the second most diagnosed cancer in the male population, MHC loci undergo [...] Read more.
The major histocompatibility complex (MHC) loci, the most polymorphic regions within the human genome, encode protein complexes responsible for antigen presentation and CD4+ and CD8+ cell activation. In prostate cancer (PCa), the second most diagnosed cancer in the male population, MHC loci undergo significant changes in their expression patterns, which affect the ability of the immune system to attack and eliminate malignant cells. The purpose of this study was to explore the genetic diversity of human leukocyte antigen (HLA)-A and HLA-B in patients with PCa and healthy controls (HCs) by performing HLA genotyping using NGS technology. The analysis highlighted statistically significant differences (p < 0.05) in the prevalence of three alleles (A*11:01, A*24:02, and B*18:01). Among the HCs analyzed, 14.89% had A*11:01, 20.21% had A*24:02, and 30.61% had B*18:01; while 5.21% of patients with PCa presented A*11:01, 9.38% presented A*24:02, 18.08% presented B*18:01. Odds ratio (OR) calculations underlined a negative association between the three alleles and the risk of PCa (OR < 1). The results presented in this study suggest a protective role of A*11:01, A*24:02, and B*18:01 in PCa. Full article
(This article belongs to the Special Issue Genetic Variations in Human Diseases)
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