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J. Pers. Med., Volume 8, Issue 1 (March 2018) – 12 articles

Cover Story (view full-size image): Institutional Review Boards (IRBS) reviewing studies that involve the return of genomic sequencing results may have a diverse array of concerns. Anticipating these concerns can help investigators to more effectively engage IRBs in discussions about the protection of research participants. The eMERGE network investigators report their experiences with the design, ethical considerations, and IRB interactions related to studies involving the return of genomic results to study participants. View the paper here.
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16 pages, 3112 KiB  
Article
Improved Labeling of Pancreatic Islets Using Cationic Magnetoliposomes
by Rita Sofia Garcia Ribeiro, Ashwini Ketkar-Atre, Ting Yin, Karim Louchami, Tom Struys, Ivo Lambrichts, Abdullah Sener, Willy Jean Malaisse, Marcel De Cuyper and Uwe Himmelreich
J. Pers. Med. 2018, 8(1), 12; https://doi.org/10.3390/jpm8010012 - 12 Mar 2018
Cited by 5 | Viewed by 8143
Abstract
Pancreatic islets (PIs) transplantation is an alternative approach for the treatment of severe forms of type 1 diabetes (T1D). To monitor the success of transplantation, it is desirable to follow the location of engrafted PIs non-invasively. In vivo magnetic resonance imaging (MRI) of [...] Read more.
Pancreatic islets (PIs) transplantation is an alternative approach for the treatment of severe forms of type 1 diabetes (T1D). To monitor the success of transplantation, it is desirable to follow the location of engrafted PIs non-invasively. In vivo magnetic resonance imaging (MRI) of transplanted PIs is a feasible cell tracking method; however, this requires labeling with a suitable contrast agent prior to transplantation. We have tested the feasibility of cationic magnetoliposomes (MLs), compared to commercial contrast agents (Endorem and Resovist), by labeling insulinoma cells and freshly isolated rat PIs. It was possible to incorporate Magnetic Ressonance (MR)-detectable amounts of MLs in a shorter time (4 h) when compared to Endorem and Resovist. MLs did not show negative effects on the PIs’ viability and functional parameters in vitro. Labeled islets were transplanted in the renal sub-capsular region of healthy mice. Hypointense contrast in MR images due to the labeled PIs was detected in vivo upon transplantation, while MR detection of PIs labeled with Endorem and Resovist was only possible after the addition of transfection agents. These findings indicate that MLs are suitable to image PIs, without affecting their function, which is promising for future longitudinal pre-clinical and clinical studies involving the assessment of PI transplantation. Full article
(This article belongs to the Special Issue Personalized Nanomedicine)
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13 pages, 1165 KiB  
Article
A Genome-Wide Association Study of Idiopathic Dilated Cardiomyopathy in African Americans
by Huichun Xu, Gerald W. Dorn II, Amol Shetty, Ankita Parihar, Tushar Dave, Shawn W. Robinson, Stephen S. Gottlieb, Mark P. Donahue, Gordon F. Tomaselli, William E. Kraus, Braxton D. Mitchell and Stephen B. Liggett
J. Pers. Med. 2018, 8(1), 11; https://doi.org/10.3390/jpm8010011 - 26 Feb 2018
Cited by 33 | Viewed by 9941
Abstract
Idiopathic dilated cardiomyopathy (IDC) is the most common form of non-ischemic chronic heart failure. Despite the higher prevalence of IDC in African Americans, the genetics of IDC have been relatively understudied in this ethnic group. We performed a genome-wide association study to identify [...] Read more.
Idiopathic dilated cardiomyopathy (IDC) is the most common form of non-ischemic chronic heart failure. Despite the higher prevalence of IDC in African Americans, the genetics of IDC have been relatively understudied in this ethnic group. We performed a genome-wide association study to identify susceptibility genes for IDC in African Americans recruited from five sites in the U.S. (662 unrelated cases and 1167 controls). The heritability of IDC was calculated to be 33% (95% confidence interval: 19–47%; p = 6.4 × 10−7). We detected association of a variant in a novel intronic locus in the CACNB4 gene meeting genome-wide levels of significance (p = 4.1 × 10−8). The CACNB4 gene encodes a calcium channel subunit expressed in the heart that is important for cardiac muscle contraction. This variant has not previously been associated with IDC in any racial group. Pathway analysis, based on the 1000 genes most strongly associated with IDC, showed an enrichment for genes related to calcium signaling, growth factor signaling, neuronal/neuromuscular signaling, and various types of cellular level signaling, including gap junction and cAMP signaling. Our results suggest a novel locus for IDC in African Americans and provide additional insights into the genetic architecture and etiology. Full article
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21 pages, 10878 KiB  
Article
Gene Environment Interactions and Predictors of Colorectal Cancer in Family-Based, Multi-Ethnic Groups
by S. Pamela K. Shiao, James Grayson, Chong Ho Yu, Brandi Wasek and Teodoro Bottiglieri
J. Pers. Med. 2018, 8(1), 10; https://doi.org/10.3390/jpm8010010 - 16 Feb 2018
Cited by 14 | Viewed by 8118
Abstract
For the personalization of polygenic/omics-based health care, the purpose of this study was to examine the gene–environment interactions and predictors of colorectal cancer (CRC) by including five key genes in the one-carbon metabolism pathways. In this proof-of-concept study, we included a total of [...] Read more.
For the personalization of polygenic/omics-based health care, the purpose of this study was to examine the gene–environment interactions and predictors of colorectal cancer (CRC) by including five key genes in the one-carbon metabolism pathways. In this proof-of-concept study, we included a total of 54 families and 108 participants, 54 CRC cases and 54 matched family friends representing four major racial ethnic groups in southern California (White, Asian, Hispanics, and Black). We used three phases of data analytics, including exploratory, family-based analyses adjusting for the dependence within the family for sharing genetic heritage, the ensemble method, and generalized regression models for predictive modeling with a machine learning validation procedure to validate the results for enhanced prediction and reproducibility. The results revealed that despite the family members sharing genetic heritage, the CRC group had greater combined gene polymorphism rates than the family controls (p < 0.05), on MTHFR C677T, MTR A2756G, MTRR A66G, and DHFR 19 bp except MTHFR A1298C. Four racial groups presented different polymorphism rates for four genes (all p < 0.05) except MTHFR A1298C. Following the ensemble method, the most influential factors were identified, and the best predictive models were generated by using the generalized regression models, with Akaike’s information criterion and leave-one-out cross validation methods. Body mass index (BMI) and gender were consistent predictors of CRC for both models when individual genes versus total polymorphism counts were used, and alcohol use was interactive with BMI status. Body mass index status was also interactive with both gender and MTHFR C677T gene polymorphism, and the exposure to environmental pollutants was an additional predictor. These results point to the important roles of environmental and modifiable factors in relation to gene–environment interactions in the prevention of CRC. Full article
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33 pages, 6143 KiB  
Review
P450 Pharmacogenetics in Indigenous North American Populations
by Lindsay M. Henderson, Katrina G. Claw, Erica L. Woodahl, Renee F. Robinson, Bert B. Boyer, Wylie Burke and Kenneth E. Thummel
J. Pers. Med. 2018, 8(1), 9; https://doi.org/10.3390/jpm8010009 - 01 Feb 2018
Cited by 22 | Viewed by 10916
Abstract
Indigenous North American populations, including American Indian and Alaska Native peoples in the United States, the First Nations, Métis and Inuit peoples in Canada and Amerindians in Mexico, are historically under-represented in biomedical research, including genomic research on drug disposition and response. Without [...] Read more.
Indigenous North American populations, including American Indian and Alaska Native peoples in the United States, the First Nations, Métis and Inuit peoples in Canada and Amerindians in Mexico, are historically under-represented in biomedical research, including genomic research on drug disposition and response. Without adequate representation in pharmacogenetic studies establishing genotype-phenotype relationships, Indigenous populations may not benefit fully from new innovations in precision medicine testing to tailor and improve the safety and efficacy of drug treatment, resulting in health care disparities. The purpose of this review is to summarize and evaluate what is currently known about cytochrome P450 genetic variation in Indigenous populations in North America and to highlight the importance of including these groups in future pharmacogenetic studies for implementation of personalized drug therapy. Full article
(This article belongs to the Special Issue Cytochrome P450 Variation in Pharmacogenomics)
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31 pages, 2646 KiB  
Review
Pharmacogenomic Impact of CYP2C19 Variation on Clopidogrel Therapy in Precision Cardiovascular Medicine
by Sherry-Ann Brown and Naveen Pereira
J. Pers. Med. 2018, 8(1), 8; https://doi.org/10.3390/jpm8010008 - 30 Jan 2018
Cited by 67 | Viewed by 20057
Abstract
Variability in response to antiplatelet therapy can be explained in part by pharmacogenomics, particularly of the CYP450 enzyme encoded by CYP2C19. Loss-of-function and gain-of-function variants help explain these interindividual differences. Individuals may carry multiple variants, with linkage disequilibrium noted among some alleles. [...] Read more.
Variability in response to antiplatelet therapy can be explained in part by pharmacogenomics, particularly of the CYP450 enzyme encoded by CYP2C19. Loss-of-function and gain-of-function variants help explain these interindividual differences. Individuals may carry multiple variants, with linkage disequilibrium noted among some alleles. In the current pharmacogenomics era, genomic variation in CYP2C19 has led to the definition of pharmacokinetic phenotypes for response to antiplatelet therapy, in particular, clopidogrel. Individuals may be classified as poor, intermediate, extensive, or ultrarapid metabolizers, based on whether they carry wild type or polymorphic CYP2C19 alleles. Variant alleles differentially impact platelet reactivity, concentration of plasma clopidogrel metabolites, and clinical outcomes. Interestingly, response to clopidogrel appears to be modulated by additional factors, such as sociodemographic characteristics, risk factors for ischemic heart disease, and drug-drug interactions. Furthermore, systems medicine studies suggest that a broader approach may be required to adequately assess, predict, preempt, and manage variation in antiplatelet response. Transcriptomics, epigenomics, exposomics, miRNAomics, proteomics, metabolomics, microbiomics, and mathematical, computational, and molecular modeling should be integrated with pharmacogenomics for enhanced prediction and individualized care. In this review of pharmacogenomic variation of CYP450, a systems medicine approach is described for tailoring antiplatelet therapy in clinical practice of precision cardiovascular medicine. Full article
(This article belongs to the Special Issue Cytochrome P450 Variation in Pharmacogenomics)
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9 pages, 255 KiB  
Article
Genetic Variations in Sweet Taste Receptor Gene Are Related to Chocolate Powder and Dietary Fiber Intake in Obese Children and Adolescents
by Marina B. Pioltine, Maria Edna De Melo, Aritânia S. Santos, Alisson D. Machado, Ariana E. Fernandes, Clarissa T. Fujiwara, Cintia Cercato and Marcio C. Mancini
J. Pers. Med. 2018, 8(1), 7; https://doi.org/10.3390/jpm8010007 - 29 Jan 2018
Cited by 19 | Viewed by 8508
Abstract
Childhood obesity is a major public health problem. It has a direct impact on the quality of life of children and adolescents, as well as on their future risk of developing chronic diseases. Dietary patterns rich in fats and sugars and lacking dietary [...] Read more.
Childhood obesity is a major public health problem. It has a direct impact on the quality of life of children and adolescents, as well as on their future risk of developing chronic diseases. Dietary patterns rich in fats and sugars and lacking dietary fibers, vitamins, and minerals, as well as lack of physical exercise have been associated with the rise of obesity prevalence. However, factors that contribute to the preference for foods rich in these nutrients are not well established. Taste is recognized as an important predictor of food choices, and polymorphisms in taste-related genes may explain the variability of taste preference and food intake. The aim of this research is to evaluate the influence of polymorphisms of the sweet taste receptor gene TAS1R2 on diet and metabolic profile in obese children and adolescents. A cross-sectional study with 513 obese children and adolescents and 135 normal-weight children was carried out. A molecular study was performed for the single nucleotide polymorphisms (SNPs) rs9701796 and rs35874116 of TAS1R2, and dietary intake, anthropometric parameters (weight, height, waist circumference, waist-to-height ratio (WHtR)), and metabolic profile (including fasting glucose, insulin, triglyceride, high-density lipoprotein (HDL)–cholesterol, and leptin levels) were analyzed. The variant rs9701796 was associated with increased waist-height ratio, as well as with a higher chocolate powder intake in obese children. The variant rs35874116 was associated with a lower dietary fiber intake. In conclusion, there was no relationship between genotypes and risk of obesity. Obese adolescents carrying the serine allele of SNP rs9701796 in TAS1R2 showed higher waist-to-height ratio and chocolate powder intake, whereas those carrying the valine allele of SNP rs35874116 in TAS1R2 were characterized by lower dietary fiber intake. Full article
(This article belongs to the Special Issue Nutrigenomics)
24 pages, 1206 KiB  
Review
Polymer Therapeutics: Biomarkers and New Approaches for Personalized Cancer Treatment
by Stuart P. Atkinson, Zoraida Andreu and María J. Vicent
J. Pers. Med. 2018, 8(1), 6; https://doi.org/10.3390/jpm8010006 - 23 Jan 2018
Cited by 17 | Viewed by 18288
Abstract
Polymer therapeutics (PTs) provides a potentially exciting approach for the treatment of many diseases by enhancing aqueous solubility and altering drug pharmacokinetics at both the whole organism and subcellular level leading to improved therapeutic outcomes. However, the failure of many polymer-drug conjugates in [...] Read more.
Polymer therapeutics (PTs) provides a potentially exciting approach for the treatment of many diseases by enhancing aqueous solubility and altering drug pharmacokinetics at both the whole organism and subcellular level leading to improved therapeutic outcomes. However, the failure of many polymer-drug conjugates in clinical trials suggests that we may need to stratify patients in order to match each patient to the right PT. In this concise review, we hope to assess potential PT-specific biomarkers for cancer treatment, with a focus on new studies, detection methods, new models and the opportunities this knowledge will bring for the development of novel PT-based anti-cancer strategies. We discuss the various “hurdles” that a given PT faces on its passage from the syringe to the tumor (and beyond), including the passage through the bloodstream, tumor targeting, tumor uptake and the intracellular release of the active agent. However, we also discuss other relevant concepts and new considerations in the field, which we hope will provide new insight into the possible applications of PT-related biomarkers. Full article
(This article belongs to the Special Issue Personalized Nanomedicine)
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2 pages, 294 KiB  
Editorial
Acknowledgement to Reviewers of Journal of Personalized Medicine in 2017
by Journal of Personalized Medicine Editorial Office
J. Pers. Med. 2018, 8(1), 5; https://doi.org/10.3390/jpm8010005 - 15 Jan 2018
Viewed by 5914
Abstract
Peer review is an essential part in the publication process, ensuring that Journal of Personalized Medicine maintains high quality standards for its published papers.[...] Full article
12 pages, 1782 KiB  
Article
Novel PAMAM-PEG-Peptide Conjugates for siRNA Delivery Targeted to the Transferrin and Epidermal Growth Factor Receptors
by Koldo Urbiola, Laura Blanco-Fernández, Manfred Ogris, Wolfgang Rödl, Ernst Wagner and Conchita Tros de Ilarduya
J. Pers. Med. 2018, 8(1), 4; https://doi.org/10.3390/jpm8010004 - 09 Jan 2018
Cited by 15 | Viewed by 8411
Abstract
The transferrin (TfR) and epidermal growth factor receptors (EGFR) are known to be overexpressed on the surface of a wide variety of tumor cells. Therefore, the peptides B6 (TfR specific) and GE11 (targeted to the EGFR) were linked to the PAMAM (polyamidoamine) structure [...] Read more.
The transferrin (TfR) and epidermal growth factor receptors (EGFR) are known to be overexpressed on the surface of a wide variety of tumor cells. Therefore, the peptides B6 (TfR specific) and GE11 (targeted to the EGFR) were linked to the PAMAM (polyamidoamine) structure via a polyethylenglycol (PEG) 2 kDa chain with the aim of improving the silencing capacity of the PAMAM-based dendriplexes. The complexes showed an excellent binding capacity to the siRNA with a maximal condensation at nitrogen/phosphate (N/P) 2. The nanoparticles formed exhibited hydrodynamic diameters below 200 nm. The zeta potential was always positive, despite the complexes containing the PEG chain in the structure showing a drop of the values due to the shielding effect. The gene silencing capacity was assayed in HeLa and LS174T cells stably transfected with the eGFPLuc cassette. The dendriplexes containing a specific anti luciferase siRNA, assayed at different N/P ratios, were able to mediate a mean decrease of the luciferase expression values of 14% for HeLa and 20% in LS174T cells, compared to an unspecific siRNA-control. (p < 0.05). In all the conditions assayed, dendriplexes resulted to be non-toxic and viability was always above 75%. Full article
(This article belongs to the Special Issue Personalized Nanomedicine)
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35 pages, 17889 KiB  
Review
Pharmacogenetics of Vascular Risk Factors in Alzheimer’s Disease
by Ramón Cacabelos, Arun Meyyazhagan, Juan C. Carril, Pablo Cacabelos and Óscar Teijido
J. Pers. Med. 2018, 8(1), 3; https://doi.org/10.3390/jpm8010003 - 03 Jan 2018
Cited by 24 | Viewed by 11086
Abstract
Alzheimer’s disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic [...] Read more.
Alzheimer’s disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC) exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Furthermore, APOE, NOS3, ACE, AGT, and CYP variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders. Full article
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18 pages, 232 KiB  
Article
Ethical Considerations Related to Return of Results from Genomic Medicine Projects: The eMERGE Network (Phase III) Experience
by Robyn Fossey, David Kochan, Erin Winkler, Joel E. Pacyna, Janet Olson, Stephen Thibodeau, John J. Connolly, Margaret Harr, Meckenzie A. Behr, Cynthia A. Prows, Beth Cobb, Melanie F. Myers, Nancy D. Leslie, Bahram Namjou-Khales, Hila Milo Rasouly, Julia Wynn, Alexander Fedotov, Wendy K. Chung, Ali Gharavi, Janet L. Williams, Lynn Pais, Ingrid Holm, Sharon Aufox, Maureen E. Smith, Aaron Scrol, Kathleen Leppig, Gail P. Jarvik, Georgia L. Wiesner, Rongling Li, Mary Stroud, Jordan W. Smoller, Richard R. Sharp and Iftikhar J. Kulloadd Show full author list remove Hide full author list
J. Pers. Med. 2018, 8(1), 2; https://doi.org/10.3390/jpm8010002 - 03 Jan 2018
Cited by 41 | Viewed by 9598
Abstract
We examined the Institutional Review Board (IRB) process at 9 academic institutions in the electronic Medical Records and Genomics (eMERGE) Network, for proposed electronic health record-based genomic medicine studies, to identify common questions and concerns. Sequencing of 109 disease related genes and genotyping [...] Read more.
We examined the Institutional Review Board (IRB) process at 9 academic institutions in the electronic Medical Records and Genomics (eMERGE) Network, for proposed electronic health record-based genomic medicine studies, to identify common questions and concerns. Sequencing of 109 disease related genes and genotyping of 14 actionable variants is being performed in ~28,100 participants from the 9 sites. Pathogenic/likely pathogenic variants in actionable genes are being returned to study participants. We examined each site’s research protocols, informed-consent materials, and interactions with IRB staff. Research staff at each site completed questionnaires regarding their IRB interactions. The time to prepare protocols for IRB submission, number of revisions and time to approval ranged from 10–261 days, 0–11, and 11–90 days, respectively. IRB recommendations related to the readability of informed consent materials, specifying the full range of potential risks, providing options for receiving limited results or withdrawal, sharing of information with family members, and establishing the mechanisms to answer participant questions. IRBs reviewing studies that involve the return of results from genomic sequencing have a diverse array of concerns, and anticipating these concerns can help investigators to more effectively engage IRBs. Full article
938 KiB  
Review
Pharmacogenomics of CYP2C9: Functional and Clinical Considerations
by Ann K. Daly, Allan E. Rettie, Douglas M. Fowler and John O. Miners
J. Pers. Med. 2018, 8(1), 1; https://doi.org/10.3390/jpm8010001 - 28 Dec 2017
Cited by 128 | Viewed by 15767
Abstract
CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several [...] Read more.
CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions. Factors relevant to clinical response to CYP2C9 substrates including inhibition, induction and genetic polymorphism are discussed in detail. In particular, we consider the issue of ethnic variation in pattern and frequency of genetic polymorphisms and clinical implications. Warfarin is the most well studied CYP2C9 substrate; recent work on use of dosing algorithms that include CYP2C9 genotype to improve patient safety during initiation of warfarin dosing are reviewed and prospects for their clinical implementation considered. Finally, we discuss a novel approach to cataloging the functional capabilities of rare ‘variants of uncertain significance’, which are increasingly detected as more exome and genome sequencing of diverse populations is conducted. Full article
(This article belongs to the Special Issue Cytochrome P450 Variation in Pharmacogenomics)
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