Diuretic–gene interaction and the risk of myocardial infarction and stroke

Abstract

This study investigates whether the interaction between diuretics and alphaadducin (ADD1) G460W or G-protein b3-subunit (GNB3) rs2301339 polymorphism modifies the risk of myocardial infarction (MI) or stroke. Data were used from the Rotterdam Study. The drug-gene interaction was determined with a Cox proportional hazard model with adjustment for each drug class as time-dependent covariates. The risk of MI in current users of low-ceiling diuretics with one or two copies of the ADD1 W-allele (hazard ration (HR) ¼ 0.92) was similar compared to the expected joint effect of the W-allele and low-ceiling diuretics on a multiplicative scale (1.04 Â 0.90 ¼ 0.94) (synergy index (SI):0.99; 95% confidence interval (CI): 0.43-2.27). No drug-gene interaction was found on the risk of stroke (SI:0.66; 95% CI:0.43-1.27). In addition, a trend towards an interaction was found between current use and the GNB3 rs230119 G/A polymorphism on the risk of MI (SI: 0.51; 95% CI: 0.23-1.15), whereas no interaction on the risk of stroke was found (SI: 0.84; 95% CI: 0.46-1.56).

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] .…”

Interaction between the Gly460Trp α-adducin gene variant and diuretics on the risk of myocardial infarction

“…Three studies [8,15,16] showed a greater BP response to hydrochlorothiazide among carriers of the Trp allele. In three studies, one performed in nonHispanic black and non-Hispanic white patients in the USA, and two in observational cohort studies in the Netherlands among whites, no relationship between the a-adducin genotypes and BP response to diuretics was found [17][18][19].…”

“…The variation of response in preventing MI and stroke has been assessed in four studies [19][20][21][22] until now. The results of these studies are inconsistent.…”

Genetic variants in the ADD1 and GNB3 genes and blood pressure response to potassium supplementation

“…Several studies have identified associations between C825T polymorphism (rs5443), rs2301339, and rs5446 of the GNB3 gene with hypertension, myocardial infarction, stroke or type 2 diabetes [8,9,13,[25][26][27]. However, no studies have examined association between these three genetic variants of the GNB3 gene and BP response to potassium-implementation.…”