A Single-Nucleotide Polymorphism in C12orf43 Region is Associated with the Risk of Coronary Artery Disease in a Pakistani Cohort.

Coronary artery disease (CAD) is one of the leading public health problems associated with mortality and morbidity in the world. It is a complex disorder influenced by both genetic and environmental factors. Atherosclerosis and elevated levels of plasma cholesterol contribute to increased risk for CAD. Other risk factors include age, hypertension, obesity, diabetes, smoking, and family history. Previous genetic studies have identified multiple polymorphisms in various genes to be associated with the risk of CAD in different populations. We aimed to examine the association of MRAS/rs9818870 and C12orf43/rs2258287 polymorphisms with the risk of CAD in a Pakistani sample. A total of 200 samples (100 cases and 100 controls) was analyzed by Allele-specific PCR. Genotypes were determined by agarose gel electrophoresis. In the current study, locus C12orf43/rs2258287 was found to be associated with the risk of CAD in the studied Pakistani cohort (OR 0.18; CI 0.08-0.37; p = 0.0001) while no association was observed for MRAS/rs9818870 (OR 1.34; CI 0.65-2.76; p = 0.42). In conclusion, the rs2258287 SNP may play an important role in the progression of CAD in the Pakistani subjects. However, future studies should be done on a larger sample size to fully establish its exact role in CAD.

Effect of genetic variation in UGT1A and ABCB1 on moxifloxacin pharmacokinetics in South African patients with tuberculosis.

AIM: We assessed the effect of genetic variability in UGT1A and ABCB1 genes on moxifloxacin pharmacokinetics. METHODS: Genotypes for selected UGT1A and ABCB1 SNPs were determined using a TaqMan® Genotyping OpenArray™ and high-resolution melt analysis for rs8175347. A nonlinear mixed-effects model was used to describe moxifloxacin pharmacokinetics. RESULTS: Genotypes of UGT1A SNPs, rs8175347 and rs3755319 (20.6% lower and 11.6% increased clearance, respectively) and ABCB1 SNP rs2032582 (40% reduced bioavailability in one individual) were significantly associated with changes in moxifloxacin pharmacokinetic parameters. CONCLUSION: Genetic variation in UGT1A as represented by rs8175347 to a lesser extent rs3755319 and the ABCB1 rs2032582 SNP is modestly associated with the interindividual variability reported in moxifloxacin pharmacokinetics and exposure. Clinical relevance of the effects of genetic variation on moxifloxacin pharmacokinetic requires further investigation.

The role of genetic analysis for predicting outcome of rheumatoid arthritis.

INTRODUCTION: Rheumatoid Arthritis (RA) varies from a mild to a severe, unremitting illness characterized by uncontrolled inflammation with consequent damage to cartilage and bone of joints. Individualized therapeutic approaches based on likely outcome would facilitate a personalized therapeutic approach. Areas covered: Genetics is known to contribute a significant component of the variability in RA outcome, estimated at 45-60%. A number of candidate gene studies have been associated with variability in radiologically assessed joint damage; however a more comprehensive genome wide analysis is required to more fully characterize the genetic basis of RA severity. Expert commentary: Genetic profiling of patient presenting with RA has the potential to aid stratification based on predicted prognosis, this would inform the clinical development of a personalized therapeutic approach. It will also result in the identification of novel mediators of tissue damage in RA.

Impact of CYP2D6 genotype on amitriptyline efficacy for the treatment of diabetic peripheral neuropathy: a pilot study.

AIM: Therapy with low-dose amitriptyline is commonly used to treat painful diabetic peripheral neuropathy. There is a knowledge gap, however, regarding the role of variable CYP2D6-mediated drug metabolism and side effects (SEs). We aimed to generate pilot data to demonstrate that SEs are more frequent in patients with variant CYP2D6 alleles. METHOD: To that end, 31 randomly recruited participants were treated with low-dose amitriptyline for painful diabetic peripheral neuropathy and their CYP2D6 gene sequenced. RESULTS: Patients with predicted normal or ultra-rapid metabolizer phenotypes presented with less SEs compared with individuals with decreased CYP2D6 activity. CONCLUSION: Hence, CYP2D6 genotype contributes to treatment outcome and may be useful for guiding drug therapy. Future investigations in a larger patient population are planned to support these preliminary findings.

Pharmacogenomics and Global Precision Medicine in the Context of Adverse Drug Reactions: Top 10 Opportunities and Challenges for the Next Decade.

In a move indicative of the enthusiastic support of precision medicine, the U.S. President Barack Obama announced the Precision Medicine Initiative in January 2015. The global precision medicine ecosystem is, thus, receiving generous support from the United States ($215 million), and numerous other governments have followed suit. In the context of precision medicine, drug treatment and prediction of its outcomes have been important for nearly six decades in the field of pharmacogenomics. The field offers an elegant solution for minimizing the effects and occurrence of adverse drug reactions (ADRs). The Clinical Pharmacogenetics Implementation Consortium (CPIC) plays an important role in this context, and it aims at specifically guiding the translation of clinically relevant and evidence-based pharmacogenomics research. In this forward-looking analysis, we make particular reference to several of the CPIC guidelines and their role in guiding the treatment of highly relevant diseases, namely cardiovascular disease, major depressive disorder, cancer, and human immunodeficiency virus, with a view to predicting and managing ADRs. In addition, we provide a list of the top 10 crosscutting opportunities and challenges facing the fields of precision medicine and pharmacogenomics, which have broad applicability independent of the drug class involved. Many of these opportunities and challenges pertain to infrastructure, study design, policy, and science culture in the early 21st century. Ultimately, rational pharmacogenomics study design and the acquisition of comprehensive phenotypic data that proportionately match the genomics data should be an imperative as we move forward toward global precision medicine.

Genetic variation in imprinted genes is associated with risk of late-onset Alzheimer's disease.

Epigenetic changes including genomic imprinting may affect risk of late-onset Alzheimer's disease (LOAD). There are >100 known imprinted genes and most of them are expressed in human brain. In this study, we examined the association of single nucleotide polymorphisms (SNPs) in 93 imprinted genes with LOAD risk in 1291 LOAD cases and 958 cognitively normal controls. We performed single-site, gene-based, and haplotype analyses. Single-site analysis showed 14 significant associations at p < 0.01. The most significant SNP (rs11770199; p = 0.0003) in single-site analysis was located on chromosome 7 in the GRB10 gene. Gene-based analyses revealed four significant associations in the WT1, ZC3H12C, DLGAP2, and GPR1 genes at p < 0.05. The haplotype analysis also revealed significant associations with three genes (ZC3H12C, DLGAP2, and GPR1). These findings suggest a possible role of imprinted genes in AD pathogenesis that show specific expression in the brain.