Abstract
AIMS: Elevated brain natriuretic peptide (BNP) and the N-terminal fragment of its pro-hormone (NT-proBNP) have become established biomarkers for heart failure and are associated with cardiovascular morbidity and mortality. Investigating sources of inter-individual heterogeneity, particularly genetic factors, could help better identify patients at risk of future cardiovascular disease. The aim of this study was to estimate the heritability of circulating NT-proBNP levels, to perform a genome-wide association study (GWAS) and gene-candidate analysis focused on NPPB-NPPA genes on these levels, and to examine their association with cardiovascular or metabolic outcomes. METHODS AND RESULTS: A total of 1555 individuals from the STANISLAS study were included. The heritability of circulating NT-proBNP levels was estimated at 15%, with seven single nucleotide polymorphisms (SNPs) reaching the significant threshold in the GWAS. All above SNPs were located on the same gene cluster constituted of MTHFR, CLCN6, NPPA, NPPB, and C1orf167. NPPA gene expression was also associated with NT-proBNP levels. Moreover, six other SNPs from NPPA-NPPB genes were associated with diastolic function (lateral e' on echocardiography) and metabolic features (glycated haemoglobin). CONCLUSIONS: The heritability of natriuretic peptides appears relatively low (15%) and mainly based on the same gene cluster constituted of MTHFR, CLCN6, NPPA, NPPB, and C1orf167. Natriuretic peptide polymorphisms are associated with natriuretic peptide levels and diastolic function. These results suggest that natriuretic peptide polymorphisms may have an impact in the early stages of cardiovascular and metabolic disease.