Genetic Contributors of Efficacy and Adverse Metabolic Effects of Chlorthalidone in African Americans from the Genetics of Hypertension Associated Treatments (GenHAT) Study.

Hypertension is a leading risk factor for cardiovascular disease mortality. African Americans (AAs) have the highest prevalence of hypertension in the United States, and to alleviate the burden of hypertension in this population, better control of blood pressure (BP) is needed. Previous studies have shown considerable interpersonal differences in BP response to antihypertensive treatment, suggesting a genetic component. Utilizing data from 4297 AA participants randomized to chlorthalidone from the Genetics of Hypertension Associated Treatments (GenHAT) study, we aimed to identify variants associated with the efficacy of chlorthalidone. An additional aim was to find variants that contributed to changes in fasting glucose (FG) in these individuals. We performed genome-wide association analyses on the change of systolic and diastolic BP (SBP and DBP) over six months and FG levels over 24 months of treatment. We sought replication in the International Consortia of Pharmacogenomics Studies. We identified eight variants statistically associated with BP response and nine variants associated with FG response. One suggestive LINC02211-CDH9 intergenic variant was marginally replicated with the same direction of effect. Given the impact of hypertension in AAs, this study implies that understanding the genetic background for BP control and glucose changes during chlorthalidone treatment may help prevent adverse cardiovascular events in this population.

CYP2D6 pharmacogenetics and phenoconversion in personalized medicine.

INTRODUCTION: CYP2D6 contributes to the metabolism of approximately 20-25% of drugs. However, CYP2D6 is highly polymorphic and different alleles can lead to impacts ranging from null to increase in activity. Moreover, there are commonly used drugs that potently inhibit the CYP2D6, thus causing 'phenoconversion' which can convert the genotypic normal metabolizer into phenotypic poor metabolizer. Despite growing literature on the clinical implications of non-normal CYP2D6 genotype and phenoconversion on patient-related outcomes, implementation of CYP2D6 pharmacogenetics and phenoconversion to guide prescribing is rare. This review focuses on providing the clinical importance of CYP2D6 pharmacogenetics and phenoconversion in precision medicine and summarizes the challenges and approaches to implement these into clinical practice. AREAS COVERED: A literature search was performed using PubMed and clinical studies documenting the effects of CYP2D6 genotypes and/or CYP2D6 inhibitors on pharmacokinetics, pharmacodynamics or treatment outcomes of CYP2D6-metabolized drugs, and studies on implementation challenges and approaches. EXPERT OPINION: Considering the extent and impact of genetic polymorphisms of CYP2D6, phenoconversion by the comedications, and contribution of CYP2D6 in drug metabolism, CYP2D6 pharmacogenetics is essential to ensure drug safety and efficacy. Utilization of proper guidelines incorporating both CYP2D6 pharmacogenetics and phenoconversion in clinical care assists in optimizing drug therapy.