Renin–Angiotensin System and α-Adducin Gene Polymorphisms and Their Relation to Responses to Antihypertensive Drugs: Results From the GENRES Study

Abstract

Common polymorphisms of ADD1, AGT, ACE, and AGTR1 do not markedly predict BP responses to amlodipine, bisoprolol, HCT, and losartan, at least in white hypertensive men.

Pharmacogenetics of the response to antihypertensive drugs

“…Although the studies varied greatly in population ancestry and selection criteria, duration, and response phenotypes, generally the fi ndings were consistent with hypotheses: individuals with "poor metabolizer" genotypes had higher plasma drug concentrations and greater BP reduction than those with "intermediate" to "ultra rapid metabolizer" genotypes [46][47][48][49][50]. Neither Gerhard et al [51] nor Suonsyrja et al [22] reported signifi cant associations with ADD1 (Gly460Trp), the former with atenolol in a study of long-term clinical end points and the latter with bisoprolol in a 4-week study of BP response. Suonsyrja et al's [22] study also found no signifi cant associations with AGT (Met235Thr), ACE (ID), or AGTR1 (1166A/C).…”

“…A2RB-angiotensin II receptor blocker; ACEI-angiotensin-converting enzyme inhibitor; BB-β-blocker; BP-blood pressure; CAD-coronary artery disease; CCB-calcium channel blocker; CHD-coronary heart disease; CVD-cardiovascular disease; ESRD-end-stage renal disease; HCTZ-hydrochlorothiazide diuretic; HF-heart failure; HTN-hypertension; LV-left ventricular; MI-myocardial infarction; PGx-pharmacogenetic; US-United States. [38] (see also [31,39] [22] (see also [24][25][26] (see also [25] † ) *Associations reported here met standards of signifi cance as defi ned by each study. † Selected references provided for context.…”

“…When considered together, there was a signifi cant trend (P = 0.008) in decreases of systolic BP (ranging from -3.4 mm Hg to -23.2 mm Hg) for different combinations of genotypes [16•, 17,18] [21] found no effect of the potassium large conductance calcium-activated channel, subfamily M, beta member 1 (KCNMB1, Glu65Lys) genotype on BP lowering with diuretics. Likewise, Suonsyrja et al [22] and van Wieren-de Wijer et al [23] reported no signifi cant pharmacogenetic interactions with diuretic treatment and variants of ADD1; angio tensinogen (AGT); angiotensin II receptor, type 1 (AGTR1); or angiotensinconverting enzyme (ACE) genes [24][25][26]. The 100,000 SNP GWAS by Turner et al [27•] identifi ed SNPs in the lysozyme gene (LYZ) and Yeats domain-containing protein 4 gene (YEATS4) that were associated with response to the diuretic in the Genetic Epidemiology of Responses to Antihypertensives study cohort.…”

“…Neither Gerhard et al [51] nor Suonsyrja et al [22] reported signifi cant associations with ADD1 (Gly460Trp), the former with atenolol in a study of long-term clinical end points and the latter with bisoprolol in a 4-week study of BP response. Suonsyrja et al's [22] study also found no signifi cant associations with AGT (Met235Thr), ACE (ID), or AGTR1 (1166A/C). Schelleman et al [52] found no β-blocker AGTR1 (C573T) interaction in the context of myocardial infarction and stroke.…”

A Physiologic Approach to the Pharmacogenomics of Hypertension

“…The ADD1 variant rs4961 has been studied extensively on its own. However, results have been conflicting as the T allele has been found to confer increased diuretic efficacy in some studies, but reduced efficacy in others 42,[75][76][77][78][79][80][81][82][83][84] .…”