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.

Greco, F. M. Del, Pattaro, C., Luchner, A., Pichler, I., Winkler, T., Hicks, A. A., Fuchsberger, C., Franke, A., Melville, S. A., Peters, A., Wichmann, H. E., Schreiber, S., Heid, I. M., Krawczak, M., Minelli, C., Wiedermann, C. J. and Pramstaller, P. P. (2011) 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. Human Molecular Genetics, 20 (8). pp. 1660-1671. DOI 10.1093/hmg/ddr035.

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Supplementary data:

Abstract

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 x 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 x 10(-03) to 9.3 x 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.

Document Type: Article
Keywords: brain natriuretic peptide amino-terminal probnp heart-failure diagnostic-accuracy genotype-imputation cardiac development chloride channels blood-pressure bnp disease
Research affiliation: Kiel University
Refereed: Yes
DOI etc.: 10.1093/hmg/ddr035
ISSN: 0964-6906
Date Deposited: 01 Nov 2012 05:05
Last Modified: 23 Jan 2013 10:03
URI: http://oceanrep.geomar.de/id/eprint/17035

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