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

Title: 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
Authors: Del Greco M, F
Pattaro, C
Luchner, A
Pichler, I
Winkler, T
Hicks, AA
Fuchsberger, C
Franke, A
Melville, SA
Peters, A
Wichmann, HE
Schreiber, S
Heid, IM
Krawczak, M
Minelli, C
Wiedermann, CJ
Pramstaller, PP
Item Type: Journal Article
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.
Issue Date: 27-Jan-2011
Date of Acceptance: 24-Jan-2011
URI: http://hdl.handle.net/10044/1/34671
DOI: http://dx.doi.org/10.1093/hmg/ddr035
ISSN: 1460-2083
Publisher: Oxford University Press
Start Page: 1660
End Page: 1671
Journal / Book Title: Human Molecular Genetics
Volume: 20
Issue: 8
Copyright Statement: © The Author 2011. Published by Oxford University Press. All rights reserved. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Adult
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
Genetics & Heredity
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:Infectious Disease Epidemiology
National Heart and Lung Institute
Faculty of Medicine



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