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

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 x 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 x 10–10), whereas the most significant SNP in POC1B/GALNT4 (rs11105306, pooled P = 1.02 x 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 pleot...

Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Johansson, A., Eriksson, N., Lindholm, D., Varenhorst, C., James, S., Syvänen, A.-C., Axelsson, T., Siegbahn, A., Barratt, B. J., Becker, R. C., Himmelmann, A., Katus, H. A., Steg, P. G., Storey, R. F., Wallentin, L., on behalf of the PLATO Invest Tags: ASSOCIATION STUDIES ARTICLE Source Type: research