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

Hum Mol Genet. 2011 Apr 15;20(8):1660-71. doi: 10.1093/hmg/ddr035. Epub 2011 Jan 27.

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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Atrial Natriuretic Factor / genetics*
  • Chloride Channels / genetics*
  • Chromosome Mapping*
  • Chromosomes, Human, Pair 1 / genetics
  • Female
  • Genome-Wide Association Study
  • Haplotypes
  • Heart Diseases / genetics
  • Humans
  • Likelihood Functions
  • Male
  • Markov Chains
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Middle Aged
  • Models, Genetic
  • Multigene Family*
  • Natriuretic Peptide, Brain / blood
  • Natriuretic Peptide, Brain / genetics*
  • Polymorphism, Single Nucleotide
  • Protein Precursors / blood
  • Protein Precursors / genetics
  • Regression Analysis

Substances

  • CLCN6 protein, human
  • Chloride Channels
  • NPPA protein, human
  • Protein Precursors
  • Natriuretic Peptide, Brain
  • Atrial Natriuretic Factor
  • Methylenetetrahydrofolate Reductase (NADPH2)