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

Autor:	Johansson Å; Uppsala Clinical Research Center and Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 752 37, Sweden, asa.johansson@igp.uu.se., Eriksson N; Uppsala Clinical Research Center and., Lindholm D; Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology., Varenhorst C; Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology., James S; Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology., Syvänen AC; Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory and., Axelsson T; Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory and., Siegbahn A; Uppsala Clinical Research Center and Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala 751 85, Sweden., Barratt BJ; AstraZeneca R&D, Alderley Park, Cheshire SK10 4TF, UK., Becker RC; Division of Cardiovascular Health and Disease, Heart, Lung and Vascular Institute, Academic Health Center, Cincinnati, OH 45267-0542, USA., Himmelmann A; AstraZeneca Research and Development, Mölndal 431 50, Sweden., Katus HA; Medizinishe Klinik, Universitätsklinikum Heidelberg, Heidelberg 69120, Germany., Steg PG; INSERM-Unité 1148, Paris 75019, France, Assistance Publique-Hôpitaux de Paris, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Paris 75018, France, Université Paris-Diderot, Sorbonne-Paris Cité, Paris 75013, France, NHLI Imperial College, ICMS, Royal Brompton Hospital, London SW3 6NP, UK and., Storey RF; Department of Cardiovascular Science, University of Sheffield, Sheffield S10 2RX, UK., Wallentin L; Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2016 Apr 01; Vol. 25 (7), pp. 1447-56. Date of Electronic Publication: 2016 Jan 21.
DOI:	10.1093/hmg/ddw012
Abstrakt:	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. (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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