Hypertension pharmacogenomics: in search of personalized treatment approaches

Abstract

Cardiovascular and renal diseases are associated with many risk factors, of which hypertension is one of the most prevalent. Worldwide, blood pressure control is only achieved in ~50% of those treated for hypertension, despite the availability of a considerable number of antihypertensive drugs from different pharmacological classes. Although many reasons exist for poor blood pressure control, a likely contributor is the inability to predict to which antihypertensive drug an individual is most likely to respond. Hypertension pharmacogenomics and other ‘omics’ technologies have the potential to identify genetic signals that are predictive of response or adverse outcome to particular drugs, and guide selection of hypertension treatment for a given individual. Continued research in this field will enhance our understanding of how to maximally deploy the various antihypertensive drug classes to optimize blood pressure response at the individual level. This Review summarizes the available literature on the most convincing genetic signals associated with antihypertensive drug responses and adverse cardiovascular outcomes. Future research in this area will be facilitated by enhancing collaboration between research groups through consortia such as the International Consortium for Antihypertensives Pharmacogenomics Studies, with the goal of translating replicated findings into clinical implementation.

Pharmacogenetics in Cardiovascular Medicine

“…89,90 Identification of PGx markers for beta blockers, thiazide diuretics and angiotensin-converting enzyme inhibitors for the treatment of hypertension and heart failure has been on the focus of intense research for the past two decades and the reader is referred to recent reviews in this area. 91–93 …”

Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide

“…5 Pharmacogenomics, the study of the influence of genomic variations on drug response, could be a useful tool to select the most effective antihypertensive therapy for an individual, based on genetic profile, once replicated drug-gene pairs have been discovered. 6 Many groups have conducted pharmacogenetic studies on BP response to TD using candidate gene(s) 7–11 or genome wide association studies (GWAS). 12–15 These studies, recently reviewed 6,16–18 , have advanced the knowledge surrounding hypertension pharmacogenomics and suggest several genetic variants that may be important determinants of response to TD.…”

“…6 Many groups have conducted pharmacogenetic studies on BP response to TD using candidate gene(s) 7–11 or genome wide association studies (GWAS). 12–15 These studies, recently reviewed 6,16–18 , have advanced the knowledge surrounding hypertension pharmacogenomics and suggest several genetic variants that may be important determinants of response to TD. Nevertheless, only a small percentage of the variability in BP response has been explained to date.…”

Pharmacogenetic Associations of β1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes)

“…Compelling pharmacogenetic data also exist for antihypertensive agents, particularly β-blockers with ADRB1 and thiazide diuretics with NEDD4L 14 .…”

“…The two most common and well-studied SNPs in ADRB1 are missense SNPs rs1801252 (A>G; Ser49Gly) and rs1801253 (G>C; Arg389Gly). Pharmacogenetic studies have extensively evaluated these SNPs with different CV response phenotypes 14, 19 . Among hypertensive individuals, homozygous carriers of the wild-type alleles with serine at codon 49 (Ser49) and arginine at codon 389 (Arg389) may experience greater BP lowering from β-blocker therapy than carriers of the minor allele (Gly49, Gly389), with effect size larger for codon 389 than codon 49 19 .…”