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

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‐proBNP) 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‐proBNP 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‐proBNP compared with the AA genotype (frequency 34%), with intermediate values observed in AGs (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 AGs. 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 AAs. CONCLUSIONS: The rs198389 G allele in the NPPB promoter is associated with elevated levels of NT‐proBNP throughout adult life, reduced blood pressure, hypertension and cardiovascular mortality, and increased lifespan.