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Del Greco, M, F.* ; Pattaro, C.* ; Luchner, A.* ; Pichler, I.* ; Winkler, T.* ; Hicks, A.A.* ; Fuchsberger, C.* ; Franke, A.* ; Melville, SA.* ; Peters, A. ; Wichmann, H.-E. ; Schreiber, S.* ; Heid, I.M. ; Krawczak, M.* ; Minelli, C.* ; Wiedermann, C.J.* ; Pramstaller, P.P.*

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.

Hum. Mol. Genet. 20, 1660-1671 (2011)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords brain natriuretic peptide; amino-terminal probnp; heart-failure; diagnostic-accuracy; genotype-imputation; cardiac development; chloride channels; blood-pressure; bnp; disease
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Journal Human Molecular Genetics
Quellenangaben Volume: 20, Issue: 8, Pages: 1660-1671 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Oxford
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)