Genome-Wide Association Analysis of Plasma B-Type Natriuretic Peptide in African Americans: The Jackson Heart Study

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 -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.