Abstract 17224: Genetic Association Study of Circulating NT-proANP in the General Community Identifies a Novel Gene Cluster Associated With Stroke
Background: Reduced N-terminal pro-atrial natriuretic peptide (NT-proANP) levels have been associated with development of hypertension, metabolic syndrome, heart failure and myocardial infarction. Genetic factors may explain up to 35-45% of unexplained inter-individual variability in NP levels. The goal of this study was to perform for the first time a genetic association study defining genomic variants that contribute to variability in NT-proANP levels in the general community.
Methods: Genotyping was performed by using the Cardio-MetaboChip, a high-density single nucleotide polymorphism (SNP) metabolic and atherosclerotic/ cardiovascular subgenome array, and by the process of imputing untyped SNPs from the 1,000 Genomes Project across the genome in 893 random individuals who served as the discovery cohort and replicated in a separate population of 891 subjects in the general community. Plasma NT-proANP1-98 levels were measured using a radioimmunoassay.
Results: There were 36 genome-wide significant SNPs (p≤3.9 X 10-7) identified in chromosome 1 in the MTHFR-CLCN6-NPPA-NPPB gene locus that were all replicated after correction for multiple testing. The top 19 SNPs were in high linkage disequilibrium with each other (r2>0.8) and represented by a tag SNP rs5063 that is nonsynonymous and located in the NPPA gene. The minor allele of this SNP (G/T, minor allele frequency T=0.058,) was associated with lower NT-proANP levels (r=-0.46, p<1.11 X 10-13 in the discovery cohort, and r=-0.47, p<3.14 X 10-14 in the replication cohort). The carriers of rs5063 were found to be at an increased risk for stroke as compared to wild-type subjects (p=0.012). NPPA rs5063 was found to be associated with stroke (hazard ratio 1.6; 95% confidence interval 1.17-2.19, p=0.004) after controlling for age, sex, diabetes, hypertension, atrial fibrillation, and serum cholesterol.
Conclusions: A genetic association study of circulating NT-proANP resulted in the identification of an association with genetic variants in the MTHFR-CLCN6-NPPA-NPPB gene cluster with replication of these results. The tag SNP representing the most significant SNPs in this region is associated with a risk of stroke in the general community after controlling for relevant clinical characteristics.
- © 2013 by American Heart Association, Inc.