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

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

Johansson, Åsa (author): Uppsala universitet,Medicinsk genetik och genomik

Eriksson, Niclas (author): Uppsala universitet,Uppsala kliniska forskningscentrum (UCR)

Lindholm, Daniel (author): Uppsala universitet,Uppsala kliniska forskningscentrum (UCR),Kardiologi

Varenhorst, Christoph (author): Uppsala universitet,Uppsala kliniska forskningscentrum (UCR)

James, Stefan (author): Uppsala universitet,Uppsala kliniska forskningscentrum (UCR),Kardiologi

Syvänen, Ann-Christine (author): Uppsala universitet,Molekylär medicin

Axelsson, Tomas (author): Uppsala universitet,Molekylär medicin

Siegbahn, Agneta (author): Uppsala universitet,Koagulation och inflammationsvetenskap

Barratt, Bryan J. (author): AstraZeneca R&D, Alderley Pk SK10 4TF, Cheshire, England.

Becker, Richard C. (author): Acad Hlth Ctr, Div Cardiovasc Hlth & Dis, Heart Lung & Vasc Inst, Cincinnati, OH 45267 USA.

Himmelmann, Anders (author): AstraZeneca Res & Dev, S-43150 Molndal, Sweden.

Katus, Hugo A. (author): Univ Klinikum Heidelberg, Med Klin, D-69120 Heidelberg, Germany.

Steg, Philippe Gabriel (author): INSERM, Unite 1148, F-75019 Paris, France.;Hop Bichat Claude Bernard, AP HP, Dept Hosp Univ FIRE, F-75018 Paris, France.;Univ Paris Diderot, Sorbonne Paris Cite, F-75013 Paris, France.;Royal Brompton Hosp, ICMS, NHLI Imperial Coll, London SW3 6NP, England.

Storey, Robert F. (author): Univ Sheffield, Dept Cardiovasc Sci, Sheffield S10 2RX, S Yorkshire, England.

Wallentin, Lars (author): Uppsala universitet,Uppsala kliniska forskningscentrum (UCR),Kardiologi

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2016-01-21
2016
English.
In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 25:7, s. 1447-1456

Related links:: https://academic.oup...; show more...; https://urn.kb.se/re...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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 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: ; NCT00391872.

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By the author/editor: Johansson, Åsa; Eriksson, Niclas; Lindholm, Daniel; Varenhorst, Chri ...; James, Stefan; Syvänen, Ann-Chr ...; show more...; Axelsson, Tomas; Siegbahn, Agneta; Barratt, Bryan J ...; Becker, Richard ...; Himmelmann, Ande ...; Katus, Hugo A.; Steg, Philippe G ...; Storey, Robert F ...; Wallentin, Lars; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medical Genetics

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Medical Biotechn ...; and Medical Biotechn ...

Articles in the publication: Human Molecular ...

By the university: Uppsala University

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

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