Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure

Abstract

We examined the association of common variants at the NPPA-NPPB locus with circulating concentrations of the natriuretic peptides, which have blood pressure-lowering properties. We genotyped SNPs at the NPPA-NPPB locus in 14,743 individuals of European ancestry, and identified associations of plasma atrial natriuretic peptide with rs5068 (P = 8 x 10(-70)), rs198358 (P = 8 x 10(-30)) and rs632793 (P = 2 x 10(-10)), and of plasma B-type natriuretic peptide with rs5068 (P = 3 x 10(-12)), rs198358 (P = 1 x 10(-25)) and rs632793 (P = 2 x 10(-68)). In 29,717 individuals, the alleles of rs5068 and rs198358 that showed association with increased circulating natriuretic peptide concentrations were also found to be associated with lower systolic (P = 2 x 10(-6) and 6 x 10(-5), respectively) and diastolic blood pressure (P = 1 x 10(-6) and 5 x 10(-5)), as well as reduced odds of hypertension (OR = 0.85, 95% CI = 0.79-0.92, P = 4 x 10(-5); OR = 0.90, 95% CI = 0.85-0.95, P = 2 x 10(-4), respectively). Common genetic variants at the NPPA-NPPB locus found to be associated with circulating natriuretic peptide concentrations contribute to interindividual variation in blood pressure and hypertension.

Figure 1. Linkage disequilibrium map across NPPA, NPPB locus in CEPH reference sample

The exon structures of NPPA and NPPB are shown schematically relative to the SNPs genotyped in the reference samples. The two genes fall on the negative strand of the human genome reference sequence and thus are in 3’ to 5’ order as shown. All SNP alleles in the text are shown according to the coding (negative) strand sequence. The pairwise linkage disequilibrium (LD) relationships among the 48 polymorphic (minor allele frequency ≥5%) SNPs passing quality control in the CEPH reference sample are shown. The linkage disequilibrium between all pairs of SNPs tested is represented at the bottom of the figure: red square indicates significant LD, white indicates weak LD, and light blue reflects inadequate power to determine LD. Three blocks of strong linkage disequilibrium are shown. The NPPA gene falls within the first block and a small region of LD breakdown between the first and second blocks. The NPPB gene lies within the second block of strong LD. Figure prepared using HaploView v2.03, defining blocks using the ‘spine of LD’ method. ³⁵ The genomic position on chromosome 1 is indicated with reference to the hg17 assembly of the human reference sequence (May 2004, NCBI build 35). The SNP numbering 1–48 corresponds to the SNPs as ordered in Supplementary Table 1.

Figure 2. ANP and BNP concentration in 7,091 individuals from Finrisk97 by genotype and by hypertension status

Genotype classes are shown from major homozygotes (left) to minor homozygotes (right). Mean plasma concentration of natriuretic peptide is shown by genotype in individuals with (red) and without (blue) hypertension. Hypertension is defined as systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg or use of antihypertensive medication. ANP units are pmol/L and BNP units are pg/mL. Standard errors of the mean are shown as black lines.