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High blood concentration of the N-terminal cleavage product of the B-type natriuretic peptide (NT-proBNP) is strongly associated with cardiac dysfunction and is increasingly used for heart failure diagnosis. To identify genetic variants associated with NT-proBNP level, we performed a genome-wide association analysis in 1325 individuals from South Tyrol, Italy, and followed up the most significant results in 1746 individuals from two German population-based studies. A genome-wide significant signal in the  MTHFR-CLCN6-NPPA-NPPB  gene cluster was replicated, after correction for multiple testing (replication one-sided  P -value = 8.4 × 10 −10 ). A conditional regression analysis of 128 single-nucleotide polymorphisms in the region of interest identified novel variants in the  CLCN6  gene as independently associated with NT-proBNP. In this locus, four haplotypes were associated with increased NT-proBNP levels (haplotype-specific combined  P -values from 8.3 × 10 −03  to 9.3 × 10 −11 ). The observed increase in the NT-proBNP level was proportional to the number of haplotype copies present (i.e. dosage effect), with an increase associated with two copies that varied between 20 and 100 pg/ml across populations. The identification of novel variants in the  MTHFR-CLCN6-NPPA-NPPB  cluster provides new insights into the biological mechanisms of cardiac dysfunction.

human molecular genetics

Genome-wide association analysis and fine mapping of NT-proBNP level provide novel insight into the role of the  MTHFR - CLCN6 - NPPA - NPPB  gene cluster