title: Genome-wide association and Mendelian randomization study of NT-proBNP in patients with acute coronary syndrome.
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.
authors.affiliation: Uppsala Clinical Research Center and Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 752 37, Sweden, asa.johansson@igp.uu.se.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Johansson
authors.affiliation: Uppsala Clinical Research Center and.
authors.forename: Niclas
authors.initials: N
authors.lastname: Eriksson
authors.affiliation: Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lindholm
authors.affiliation: Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology.
authors.forename: Christoph
authors.initials: C
authors.lastname: Varenhorst
authors.affiliation: Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology.
authors.forename: Stefan
authors.initials: S
authors.lastname: James
authors.affiliation: Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory and.
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.affiliation: Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory and.
authors.forename: Tomas
authors.initials: T
authors.lastname: Axelsson
authors.affiliation: Uppsala Clinical Research Center and Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala 751 85, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Siegbahn
authors.affiliation: AstraZeneca R&D, Alderley Park, Cheshire SK10 4TF, UK.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Barratt
authors.affiliation: Division of Cardiovascular Health and Disease, Heart, Lung and Vascular Institute, Academic Health Center, Cincinnati, OH 45267-0542, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Becker
authors.affiliation: AstraZeneca Research and Development, Mölndal 431 50, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Himmelmann
authors.affiliation: Medizinishe Klinik, Universitätsklinikum Heidelberg, Heidelberg 69120, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: 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.
authors.forename: Philippe Gabriel
authors.initials: PG
authors.lastname: Steg
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Storey
authors.affiliation: Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics; D020097:Natriuretic Peptide, Brain / Q000097:blood* / Q000235:genetics; D010446:Peptide Fragments / Q000097:blood* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D027682:Cation Transport Proteins; D018797:Cell Cycle Proteins; D017350:N-Acetylgalactosaminyltransferases; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C000592372:POC1B protein, human; C530151:SLC39A8 protein, human; C109794:pro-brain natriuretic peptide (1-76)