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.
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.
authors.affiliation: Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Del Greco M
authors.forename: Cristian
authors.initials: C
authors.lastname: Pattaro
authors.forename: Andreas
authors.initials: A
authors.lastname: Luchner
authors.forename: Irene
authors.initials: I
authors.lastname: Pichler
authors.forename: Thomas
authors.initials: T
authors.lastname: Winkler
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hicks
authors.forename: Christian
authors.initials: C
authors.lastname: Fuchsberger
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Scott A
authors.initials: SA
authors.lastname: Melville
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.forename: H Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Iris M
authors.initials: IM
authors.lastname: Heid
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
authors.forename: Cosetta
authors.initials: C
authors.lastname: Minelli
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Wiedermann
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
mesh_terms: D000328:Adult; D000368:Aged; D009320:Atrial Natriuretic Factor / Q000235:genetics*; D018118:Chloride Channels / Q000235:genetics*; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006331:Heart Diseases / Q000235:genetics; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D008390:Markov Chains; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D008957:Models, Genetic; D005810:Multigene Family; D020097:Natriuretic Peptide, Brain / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011498:Protein Precursors / Q000097:blood / Q000235:genetics; D012044:Regression Analysis
chemical_list: C097539:CLCN6 protein, human; D018118:Chloride Channels; C472955:NPPA protein, human; D011498:Protein Precursors; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D042965:Methylenetetrahydrofolate Reductase (NADPH2)