Novel genetic approach to investigate the role of plasma secretory phospholipase a2 (spla2)-v isoenzyme in coronary heart disease

Michael V. Holmes, Holly J. Exeter, Lasse Folkersen, Christopher P. Nelson, Montse Guardiola, Jackie A. Cooper, Reecha Sofat, S. Matthijs Boekholdt, Kay Tee Khaw, Ka Wah Li, Andrew J.P. Smith, Ferdinand Van't Hooft, Per Eriksson, Anders Franco-Cereceda, Folkert W. Asselbergs, Jolanda M.A. Boer, N. Charlotte Onland-Moret, Marten Hofker, Jeanette Erdmann, Mika KivimakiMeena Kumari, Alex P. Reiner, Brendan J. Keating, Steve E. Humphries, Aroon D. Hingorani, Ziad Mallat, Nilesh J. Samani, Philippa J. Talmud*

*Korrespondierende/r Autor/-in für diese Arbeit
18 Zitate (Scopus)

Abstract

Background-Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. Although observational studies show a strong association between elevated sPLA2 activity and CHD, no assay to measure sPLA2-V levels exists, and the only evidence linking the sPLA2-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA2-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 sPLA2-V levels. We tested the association of this SNP with sPLA2 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=5.1×10-6). There was no association of rs525380C>A with plasma sPLA2 activity (difference in geometric mean of sPLA2 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 sPLA2-V levels) and CHD events. The evidence does not support a causal role for sPLA2-V in CHD.

OriginalspracheEnglisch
ZeitschriftCirculation: Cardiovascular Genetics
Jahrgang7
Ausgabenummer2
Seiten (von - bis)144-150
Seitenumfang7
ISSN1942-325X
DOIs
PublikationsstatusVeröffentlicht - 01.04.2014

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  • Querschnittsbereich: Medizinische Genetik

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