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.

TitleGenome-wide association analysis and fine mapping of NT-proBNP level provide novel insight into the role of the MTHFR-CLCN6-NPPA-NPPB gene cluster.
Publication TypeJournal Article
Year of Publication2011
AuthorsDel Greco M F, Pattaro C, Luchner A, Pichler I, Winkler T, Hicks AA, Fuchsberger C, Franke A, Melville SA, Peters A, H Wichmann E, Schreiber S, Heid IM, Krawczak M, Minelli C, Wiedermann CJ, Pramstaller PP
JournalHum Mol Genet
Volume20
Issue8
Pagination1660-71
Date Published2011 Apr 15
ISSN1460-2083
KeywordsAdult, Aged, Atrial Natriuretic Factor, Chloride Channels, Chromosome Mapping, Chromosomes, Human, Pair 1, Female, Genome-Wide Association Study, Haplotypes, Heart Diseases, Humans, Likelihood Functions, Male, Markov Chains, Methylenetetrahydrofolate Reductase (NADPH2), Middle Aged, Models, Genetic, Multigene Family, Natriuretic Peptide, Brain, Polymorphism, Single Nucleotide, Protein Precursors, Regression Analysis
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 × 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.

DOI10.1093/hmg/ddr035
Alternate JournalHum. Mol. Genet.
PubMed ID21273288
PubMed Central IDPMC3063986
Grant List1 R01 DK075787-01A1 / DK / NIDDK NIH HHS / United States

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