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Holmes, M.V.* ; Exeter, H.J.* ; Folkersen, L.* ; Nelson, C.P.* ; Guardiola, M.* ; Cooper, J.A.* ; Sofat, R.* ; Boekholdt, S.M.* ; Khaw, K.T.* ; Li, K.W.* ; Smith, A.J.* ; van't Hooft, F.M.* ; Eriksson, P.* ; Franco-Cereceda, A.* ; Asselbergs, F.W.* ; Boer, J.M.* ; Onland-Moret, N.C.* ; Hofker, M.H.* ; Erdmann, J.* ; Kivimaki, M.* ; Kumari, M.* ; Reiner, A.P.* ; Keating, B.J.* ; Humphries, S.E.* ; Hingorani, A.D.* ; Mallat, Z.* ; Samani, N.J.* ; Talmud, P.J.* ; CARDIoGRAM Consortium (Döring, A. ; Illig, T. ; Klopp, N. ; Meisinger, C. ; Meitinger, T. ; Peters, A. ; Wichmann, H.-E.)

Novel genetic approach to investigate the role of plasma secretory phospholipase A2 (sPLA(2))-V isoenzyme in coronary heart disease modified mendelian randomization analysis using PLA2G5 expression levels.

Circ. Cardiovasc. Genet. 7, 144-150 (2014)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Background- Secretory phospholipase A(2) (sPLA(2)) enzymes are considered to play a role in atherosclerosis. sPLA(2) activity encompasses several sPLA(2) isoenzymes, including sPLA(2)-V. Although observational studies show a strong association between elevated sPLA(2) activity and CHD, no assay to measure sPLA(2)-V levels exists, and the only evidence linking the sPLA(2)-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA(2)-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA(2)-V in coronary heart disease (CHD) pathogenesis. Methods and Results- Using data from the Advanced Study of Aortic Pathology, we identified the single-nucleotide polymorphism in PLA2G5 showing the strongest association with PLA2G5 mRNA expression levels as a proxy for sPLA(2)-V levels. We tested the association of this SNP with sPLA(2) activity and CHD events in 4 prospective and 14 case-control studies with 27 230 events and 70 500 controls. rs525380C > A showed the strongest association with PLA2G5 mRNA expression (P=5.1x10(-6)). There was no association of rs525380C > A with plasma sPLA(2) activity (difference in geometric mean of sPLA(2) activity per rs525380 A-allele 0.4% (95% confidence intervals [-0.9%, 1.6%]; P=0.56). In meta-analyses, the odds ratio for CHD per A-allele was 1.02 (95% confidence intervals [0.99, 1.04]; P=0.20). Conclusions- This novel approach for single-nucleotide polymorphism selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead single-nucleotide polymorphism for PLA2G5 expression, a surrogate for sPLA(2)-V levels) and CHD events. The evidence does not support a causal role for sPLA(2)-V in CHD.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Mendelian Randomization Analysis; Group-v; Cardiovascular-disease; Artery-disease; Epic-norfolk; Healthy-men; A(2); Association; Atherosclerosis; Events; Risk
ISSN (print) / ISBN 1942-325X
e-ISSN 1942-3268
Journal Circulation: Cardiovascular Genetics
Quellenangaben Volume: 7, Issue: 2, Pages: 144-150 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Hagerstown, Md
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Institute of Human Genetics (IHG)