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

J Am Heart Assoc. 2017 Mar 24;6(4):e005257. doi: 10.1161/JAHA.116.005257.

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-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.

Keywords: NPPB; N‐terminal pro–B‐type; blood pressure; hypertension; mortality; natriuretic peptide; polymorphism; rs198389; single nucleotide polymorphism.

Publication types

  • Multicenter Study
  • Observational Study

MeSH terms

  • African Americans / genetics
  • Blood Pressure / genetics*
  • Chi-Square Distribution
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Hypertension / ethnology
  • Hypertension / genetics*
  • Hypertension / mortality
  • Hypertension / physiopathology
  • Kaplan-Meier Estimate
  • Linear Models
  • Longevity / genetics
  • Male
  • Middle Aged
  • Natriuretic Peptide, Brain / blood
  • Natriuretic Peptide, Brain / genetics*
  • Odds Ratio
  • Peptide Fragments / blood*
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Predictive Value of Tests
  • Promoter Regions, Genetic*
  • Prospective Studies
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • United States
  • Up-Regulation

Substances

  • Peptide Fragments
  • pro-brain natriuretic peptide (1-76)
  • Natriuretic Peptide, Brain