Genome-Wide Association Analysis of Plasma B–Type Natriuretic Peptide in Blacks

Abstract

Background Numerous experimental studies suggest that B-type natriuretic peptide (BNP) is cardioprotective, yet in clinical studies, higher plasma BNP concentrations have been associated with incident cardiovascular disease and higher left ventricular mass (LVM). Genetic association studies may allow us to determine the true causal directions without confounding by compensatory mechanisms. Methods and Results We performed meta-analysis of two genome-wide association (GWA) results from a total of 2,790 African Americans. We assumed an additive genetic model in association analysis of imputed 2.5 million SNP dosages with residuals generated from multivariable-adjusted logarithmically-transformed BNP controlling for relevant covariates and population stratification. Two loci were genome-wide significant, a candidate gene locus NPPB (rs198389, p-value=1.18×10−09) and novel missense variant in the KLKB1 locus (rs3733402, p-value=1.75×10−11) that explained 0.4% and 1.9% of variation in log BNP concentration, respectively. The observed increase in BNP concentration was proportional to the number of effect allele copies, an average of 8.1 pg/dl increase associated with two allele copies. SNPs in this loci were subsequently cross-checked with GWA results for the aldosterone-to-renin ratio in individuals of European ancestry, and only rs3733402 was genome-wide significant (p<5.0×10−8), suggesting possible shared genetic architecture for these two pathways. Other statistically significant relations for these SNPs included: rs198389 with systolic blood pressure in blacks (COGENT consortium) rs198389 and rs3733402 with LVM in whites (EchoGEN consortium). Conclusions These findings improve our knowledge of the genetic basis of BNP variation in African Americans, demonstrate possible shared allelic architecture for BNP with ARR and motivate further studies of underlying mechanisms.

Plasma Kallikrein Inhibitors in Cardiovascular Disease

“…Furthermore, in another study, the single nucleotide polymorphism rs4253311 in kallikrein B gene was associated with brain natriuretic peptide levels in African-Americans at a genome-wide significance. 143 Overall, these data strongly support the notion that plasma KKS functions with the RAS and the brain natriuretic peptide signaling pathways to regulate the cardiovascular system.…”

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

“…Meirhaeghe et al 3 showed that the G allele was associated with a 1.8-fold higher level of promoter activity versus the A allele in cultured cells. At least 7 independent racially diverse human population studies have shown that the minor allele of rs198389 SNP is associated with elevated mean levels of NT-proBNP and/or BNP [3][4][5][6][7][8][9] with similar effect size observed for NT-proBNP and BNP levels. 6 The minor allele of rs198389 (G allele; higher BNP levels) has been associated with reduced ventricular dysfunction following coronary artery bypass grafting, 10 reduced hospital readmissions, and lower E/E 1 in patients after myocardial infarction (MI), 8 and a lower risk of developing type 2 diabetes mellitus.…”

“…3,11,12 The minor allele of rs198389 was recently found to be modestly associated with reduced systolic BP (SBP) in a meta-analysis of African Americans. 7 Minor alleles of SNPs in the NPPA gene, associated with both increased atrial NP and BNP levels, unlike specific variants in the NPPB gene, have previously been associated with lower BP and incident hypertension 8,13 in primarily white individuals. Previous genetic association studies looking at cardiovascular outcomes have been small in size or with limited duration of follow-up.…”

A genome-wide association meta-analysis on apolipoprotein A-IV concentrations

“…KLKB1 encodes the glycoprotein plasma kallikrein (also known “Fletcher factor” (28)), which acts as a proteolytic activator of several vasoactive and circulating peptides (kinins) (29,30). Accordingly, SNPs in KLKB1 showed genome-wide associations with vasoactive peptides (plasma bradykinin (31,32), active renin (rs3733402) (33), BNP in Blacks (34), aldosterone/renin ratio in Europeans (34), MR-pro-ADM and CT-pro-ET-1 (rs4253238 (35), r 2  =   0.81 with our tophit). Of note, F11 is a paralog of KLKB1 and codes for the coagulation factor XI.…”