期刊
HUMAN MOLECULAR GENETICS
卷 20, 期 8, 页码 1660-1671出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddr035
关键词
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资金
- Ministero della Salute [RF-PAB-2006-342336]
- Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bozen/Bolzano
- South Tyrolean Sparkasse Foundation
- European Union [LSHG-CT-2006-018947]
- German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN)
- Ministry of Science, Commerce and Transportation of the State of Schleswig-Holstein
- German Federal Ministry of Education and Research (BMBF)
- NIH
- Children's Hospital, Boston, USA [1 R01 DK075787-01A1]
- German National Genome Research Net NGFN2 and NGFNplus [01GS0823]
- Munich Center of Health Sciences
- Kompetenznetz Herzinsuffizienz (German Heart Failure Network)
- Federal Ministry of Education and Research (BMBF)
- Helmholtz Research Center Munchen for Environmental Health
- State of Bavaria
- European Academy Bozen/Bolzano (EURAC), Bolzano, Italy
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 x 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 x 10(-03) to 9.3 x 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.
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