The Future of Pharmacogenetics in the Treatment of Hypertension

Hypertension (HTN) is one of the most common, serious health conditions worldwide, and is responsible for significant morbidity and mortality, through its contribution to vascular disease, congestive heart failure, cerebrovascular disease and kidney failure. In USA, it is estimated to affect almost 80 million Americans. Despite the availability of multiple drugs to treat HTN, rates of control of blood pressure (BP) are less than 50%, and interindividual variability of BP response to different agents is high. While certain demographic factors such as age, gender and race may help guide the selection of one antihypertensive agent over another, to a large extent the strategy that patients receive is based on trial and error. The sequencing of the human genome in 2003 was a major medical breakthrough and ushered in hopes for an individualized HTN treatment approach for patients. Not only could genetic information be used to diagnose or understand the pathophysiology of disease, but the field of pharmacogenomics brought the promise of tailoring individual drugs and their dosage to each individual’s genetic background. The Clinical Pharmacogenomics Implementation Consortium (CPIC) is an organization which reviews the large and growing pharmacogenomics published datasets to develop specific recommendations for clinical application [1]. Currently, CPIC lists specific recommendations for 35 drugs, including warfarin, clopidogrel, codeine and amitriptyline among others, in whom genetic testing can guide dosing strategy and selection of specific agents, with the hope that this strategy improves effectiveness and/or decreases adverse events. However, current CPIC guidelines include limited information and no firm recommendations about genetic testing for any antihypertensive drug. Genetic variation in the CYP2D6 gene impacts metoprolol metabolism, and the Dutch Pharmacogenomic Working Group has recommended CYP2D6 screening be used when metoprolol is prescribed, marking the only published pharmacogenomic guideline pertaining to antihypertensives [2]. Despite a large and growing number of published studies, pharmacogenetics research has found that multiple genetic variants have a modest influence on individual response to different antihypertensive medications, consistent with hypertension being a complex medical condition where hundreds of genes influence BP response in a small way [3]. The field of HTN pharmacogenomics has generated some conflicting and inconsistent findings with regard to BP response to antihypertensive medication, so it is important to define the biologic rationale behind the genetic associations found. A concise summary of genetic variants affecting antihypertensive response is given in Table 1. NEDD4L affects the expression of renal distal tubular sodium channels such as ENaC through ubiquitination. The G allele at rs414960 is associated with salt-sensitive hypertension, lower plasma renin levels and greater BP response to thiazide diuretics in analysis of three independent clinical trial cohorts: NORDIL, PEAR and INVEST. The NORDIL and INVEST studies found fewer cardiovascular events in hypertensive carriers of the G allele in those treated with thiazide diuretics [4]. The gene ADRB1 has two independent SNPs, rs1801252 and rs1801253, which lead to amino acid substitutions affecting β-1 receptor function, BP response to beta-blockers and differential effects on patient survival when atenolol was compared with verapamil therapy (hazard ratio of 2.31) [5].