Genome-wide association and Mendelian randomization study of NT-proBNP in patients with acute coronary syndrome

Hum Mol Genet. 2016 Apr 1;25(7):1447-56. doi: 10.1093/hmg/ddw012. Epub 2016 Jan 21.

Abstract

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a strong predictor of mortality in coronary artery disease and is widely employed as a prognostic biomarker. However, a causal relationship between NT-proBNP and clinical endpoints has not been established. We have performed a genome-wide association and Mendelian randomization study of NT-proBNP. We used a discovery set of 3740 patients from the PLATelet inhibition and patient Outcomes (PLATO) trial, which enrolled 18 624 patients with acute coronary syndrome (ACS). A further set of 5492 patients, from the same trial, was used for replication. Genetic variants at two novel loci (SLC39A8 and POC1B/GALNT4) were associated with NT-proBNP levels and replicated together with the previously known NPPB locus. The most significant SNP (rs198389, pooled P = 1.07 × 10(-15)) in NPPB interrupts an E-box consensus motif in the gene promoter. The association in SLC39A8 is driven by a deleterious variant (rs13107325, pooled P = 5.99 × 10(-10)), whereas the most significant SNP in POC1B/GALNT4 (rs11105306, pooled P = 1.02 × 10(-16)) is intronic. The SLC39A8 SNP was associated with higher risk of cardiovascular (CV) death (HR = 1.39, 95% CI: 1.08-1.79, P = 0.0095), but the other loci were not associated with clinical endpoints. We have identified two novel loci to be associated with NT-proBNP in patients with ACS. Only the SLC39A8 variant, but not the NPPB variant, was associated with a clinical endpoint. Due to pleotropic effects of SLC39A8, these results do not suggest that NT-proBNP levels have a direct effect on mortality in ACS patients. PLATO Clinical Trial Registration: www.clinicaltrials.gov; NCT00391872.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Coronary Syndrome / blood
  • Acute Coronary Syndrome / genetics*
  • Cation Transport Proteins / genetics*
  • Cell Cycle Proteins / genetics
  • Genome-Wide Association Study*
  • Humans
  • Mendelian Randomization Analysis*
  • Middle Aged
  • N-Acetylgalactosaminyltransferases / genetics
  • Natriuretic Peptide, Brain / blood*
  • Natriuretic Peptide, Brain / genetics
  • Peptide Fragments / blood*
  • Peptide Fragments / genetics
  • Polymorphism, Single Nucleotide*
  • Polypeptide N-acetylgalactosaminyltransferase

Substances

  • Cation Transport Proteins
  • Cell Cycle Proteins
  • POC1B protein, human
  • Peptide Fragments
  • SLC39A8 protein, human
  • pro-brain natriuretic peptide (1-76)
  • Natriuretic Peptide, Brain
  • N-Acetylgalactosaminyltransferases

Associated data

  • ClinicalTrials.gov/NCT00391872