PON1 Q192R genetic variant and response to clopidogrel and prasugrel: pharmacokinetics, pharmacodynamics, and a meta-analysis of clinical outcomes.

Clopidogrel and prasugrel are antiplatelet therapies commonly used to treat patients with cardiovascular disease. They are both pro-drugs requiring biotransformation into active metabolites. It has been proposed that a genetic variant Q192R (rs662 A>G) in PON1 significantly alters the biotransformation of clopidogrel and affects clinical outcomes; however, this assertion has limited support.

Genome-Wide Association Study of Serum Creatinine Levels during Vancomycin Therapy.

Vancomycin, a commonly used antibiotic, can be nephrotoxic. Known risk factors such as age, creatinine clearance, vancomycin dose / dosing interval, and concurrent nephrotoxic medications fail to accurately predict nephrotoxicity. To identify potential genomic risk factors, we performed a genome-wide association study (GWAS) of serum creatinine levels while on vancomycin in 489 European American individuals and validated findings in three independent cohorts totaling 439 European American individuals.

Integrating EMR-linked and in vivo functional genetic data to identify new genotype-phenotype associations.

The coupling of electronic medical records (EMR) with genetic data has created the potential for implementing reverse genetic approaches in humans, whereby the function of a gene is inferred from the shared pattern of morbidity among homozygotes of a genetic variant. We explored the feasibility of this approach to identify phenotypes associated with low frequency variants using Vanderbilt's EMR-based BioVU resource. We analyzed 1,658 low frequency non-synonymous SNPs (nsSNPs) with a minor allele frequency (MAF)<10% collected on 8,546 subjects.

Biobanks and electronic medical records: enabling cost-effective research.

The use of electronic medical record data linked to biological specimens in health care settings is expected to enable cost-effective and rapid genomic analyses. Here, we present a model that highlights potential advantages for genomic discovery and describe the operational infrastructure that facilitated multiple simultaneous discovery efforts.

Whole-exome sequencing in familial atrial fibrillation.

Aims: Positional cloning and candidate gene approaches have shown that atrial fibrillation (AF) is a complex disease with familial aggregation. Here, we employed whole-exome sequencing (WES) in AF kindreds to identify variants associated with familial AF.

Methods And Results: WES was performed on 18 individuals in six modestly sized familial AF kindreds.

Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome.

Objectives: The aim of this study was to test the hypothesis that rare variants are associated with drug-induced long QT interval syndrome (diLQTS) and torsades de pointes.

Background: diLQTS is associated with the potentially fatal arrhythmia torsades de pointes. The contribution of rare genetic variants to the underlying genetic framework predisposing to diLQTS has not been systematically examined.

Common SCN10A variants modulate PR interval and heart rate response during atrial fibrillation.

Aims: SCN10A encodes the sodium channel Nav1.8 implicated by genome-wide association studies as a modulator of atrioventricular conduction (PR interval). In a cohort of patients with atrial fibrillation (AF), we examined whether there was an association between common variants in SCN10A and both the PR interval during normal sinus rhythm and the heart rate response during AF.

A KCNJ8 mutation associated with early repolarization and atrial fibrillation.

Aim: The Kir 6.1 K(atp) channel is believed to play an important role in ventricular repolarization as determined from both functional and genetic studies of the potassium inwardly-rectifying channel, subfamily J, member 8 (KCNJ8)-S422L missense mutation in patients with J-wave syndromes. Although Kir6.

Characterization of genome-wide association-identified variants for atrial fibrillation in African Americans.

Background: Despite a greater burden of risk factors, atrial fibrillation (AF) is less common among African Americans than European-descent populations. Genome-wide association studies (GWAS) for AF in European-descent populations have identified three predominant genomic regions associated with increased risk (1q21, 4q25, and 16q22). The contribution of these loci to AF risk in African American is unknown.

Genetic determinants of response to cardiovascular drugs.

Purpose Of Review: To survey genetic variation contributing to variable responsiveness and toxicity to important cardiovascular drugs and highlight recent developments in the field of cardiovascular pharmacogenomics and personalized medicine.

Recent Findings: Previously recognized pharmacogenomic associations with drug efficacy have been further validated (e.g.

Predicting warfarin dosage in European-Americans and African-Americans using DNA samples linked to an electronic health record.

Aim: Warfarin pharmacogenomic algorithms reduce dosing error, but perform poorly in non-European-Americans. Electronic health record (EHR) systems linked to biobanks may allow for pharmacogenomic analysis, but they have not yet been used for this purpose.

Patients & Methods: We used BioVU, the Vanderbilt EHR-linked DNA repository, to identify European-Americans (n = 1022) and African-Americans (n = 145) on stable warfarin therapy and evaluated the effect of 15 pharmacogenetic variants on stable warfarin dose.