An NPPB Promoter Polymorphism Associated With Elevated N‐Terminal pro–B‐Type Natriuretic Peptide and Lower Blood Pressure, Hypertension, and Mortality

Abstract

Background Elevated B‐type natriuretic peptide ( BNP ) levels are associated with heart failure and increased mortality in the general population. We investigated rs198389, a functional variant in the promoter region of the BNP gene ( NPPB ), in patients from the Atherosclerosis Risk in Communities Study to investigate associations with N‐terminal pro‐BNP (NT‐pro BNP) levels and outcomes. Methods and Results A total of 11 361 black and white patients with rs198389 genotyping attended visit 1 (aged 45–64 years; 1987–1989), with follow‐up visits occurring every 3 years (visit 2–visit 4, 1990–1999), followed by visit 5 (2011–2013). NT ‐pro BNP levels were measured at visits 2, 4, and 5. At visit 2, the GG genotype (frequency 18%) was associated with a 41% higher mean plasma level of NT ‐pro BNP compared with the AA genotype (frequency 34%), with intermediate values observed in AG s ( P =4.2×10 −52 ). The GG genotype was associated with reduced systolic blood pressure (−1.6 mm Hg, P =0.006), diastolic blood pressure (−1 mm Hg, P =0.003), antihypertension medication use (odds ratio, 0.85; 95% CI , 0.74–0.97 [ P =0.02]), and hypertension (odds ratio, 0.81; 95% CI , 0.72–0.92 [ P =0.002]) compared with the AA genotype with intermediate values in AG s. These relationships persisted throughout subsequent visits. After a median follow‐up of 23 years, there were 4031 deaths. With and without covariate adjustment, the GG genotype was associated with modestly lower mortality (hazard ratio, 0.86; 95% CI, 0.78–0.95), primarily reflective of cardiovascular death (hazard ratio, 0.75; 95% CI, 0.61–0.92), and increased residual lifespan of 8 months from 50 years of age ( P =0.02) versus AA s. Conclusions The rs198389 G allele in the NPPB promoter is associated with elevated levels of NT ‐pro BNP throughout adult life, reduced blood pressure, hypertension and cardiovascular mortality, and increased lifespan.