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

Autor: Christian Fuchsberger, Andrew A. Hicks, Irene Pichler, Scott A. Melville, Fabiola Del Greco M, Christian J. Wiedermann, Stefan Schreiber, Andreas Luchner, Iris M. Heid, Cristian Pattaro, Michael Krawczak, Peter P. Pramstaller, Cosetta Minelli, Annette Peters, Andre Franke, Thomas W. Winkler, H.-Erich Wichmann
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Adult
Male
Heart Diseases
Locus (genetics)
Single-nucleotide polymorphism
Genome-wide association study
030204 cardiovascular system & hematology
Polymorphism
Single Nucleotide
03 medical and health sciences
0302 clinical medicine
Gene mapping
Chloride Channels
brain natriuretic peptide
amino-terminal probnp
heart-failure
diagnostic-accuracy
genotype-imputation
cardiac development
chloride channels
blood-pressure
bnp
disease
Gene cluster
Natriuretic Peptide
Brain
Genetics
Humans
Protein Precursors
Association Studies Article
Molecular Biology
Genetics (clinical)
Methylenetetrahydrofolate Reductase (NADPH2)
030304 developmental biology
Genetic association
Aged
Genetics & Heredity
0303 health sciences
Likelihood Functions
biology
Models
Genetic
Haplotype
Chromosome Mapping
General Medicine
11 Medical And Health Sciences
Middle Aged
06 Biological Sciences
Markov Chains
Haplotypes
Chromosomes
Human
Pair 1
Methylenetetrahydrofolate reductase
Multigene Family
biology.protein
Regression Analysis
Female
Atrial Natriuretic Factor
Genome-Wide Association Study
Zdroj: Hum. Mol. Genet. 20, 1660-1671 (2011)
Human Molecular Genetics
Popis: 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.
Databáze: OpenAIRE
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