The −344T>C promoter variant of the gene for aldosterone synthase (CYP11B2) is not associated with cardiovascular risk in a prospective study of UK healthy men

Introduction: The tissue renin-angiotensin system is implicated in the pathogenesis of coronary artery disease (CAD). As locally synthesised aldosterone is a potential mediator of CAD, we have sought an association of the −344T>C variant of the aldosterone synthase (CYP11B2) gene with CAD events. Methods: Subjects comprised of the Second Northwick Park Heart Study (NPHSII), a prospective study of unrelated, healthy middle-aged Caucasian males. CAD events were recorded in 2490 subjects, and defined as a sudden cardiac death, myocardial infarction or coronary artery revascularisation procedure. Mean follow-up was 10.8 years. Aldosterone synthase genotype was determined in 2490 subjects. Power calculation suggests that we have 80% power (at a significance level of 0.05) to detect a difference in hazard ratio (HR) between homozygote groups of 0.45. Results: One hundred and eighty-seven CAD events were recorded in 2490 subjects. In the group overall, CAD events were independent of genotype with adjusted hazard ratios being 1.00 versus 1.25 versus 0.80 for TT versus TC versus CC genotypes, respectively, P=0.07. Genotype interactions with smoking and blood pressure were sought. Whilst CAD events were independent of genotype amongst non-smokers, CC genotype in smokers was associated with a reduced risk HR 2.02 versus 2.28 versus 0.82 for TT versus TC versus CC genotypes, P=0.05 (HR for TT + TC versus CC were 1.77 versus 0.67, P=0.02). This apparent interaction remained after adjustment for conventional risk factors. No such interaction was found with blood pressure. Conclusions: Aldosterone synthase genotype is unrelated to overall CAD events risk. A possible interaction with smoking requires confirmation.