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
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 (, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Adult
Atrial Natriuretic Factor
Chloride Channels
Chromosome Mapping
Chromosomes, Human, Pair 1
Genome-Wide Association Study
Heart Diseases
Likelihood Functions
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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