Pulse lineResearch With Heart Logo

Novel genetic approach to investigate the role of plasma secretory phospholipase A2 (sPLA2)-V isoenzyme in coronary heart disease: modified Mendelian randomization analysis using PLA2G5 expression levels.

TitleNovel genetic approach to investigate the role of plasma secretory phospholipase A2 (sPLA2)-V isoenzyme in coronary heart disease: modified Mendelian randomization analysis using PLA2G5 expression levels.
Publication TypeJournal Article
Year of Publication2014
AuthorsHolmes MV, Exeter HJ, Folkersen L, Nelson CP, Guardiola M, Cooper JA, Sofat R, S Boekholdt M, Khaw K-T, Li K-W, Smith AJP, Hooft FVan't, Eriksson P, Franco-Cereceda A, Asselbergs FW, Boer JMA, Onland-Moret CN, Hofker M, Erdmann J, Kivimaki M, Kumari M, Reiner AP, Keating BJ, Humphries SE, Hingorani AD, Mallat Z, Samani NJ
Secondary AuthorsTalmud PJ
Corporate AuthorsCARDIoGRAM Consortium
JournalCirc Cardiovasc Genet
Volume7
Issue2
Pagination144-50
Date Published2014 Apr
ISSN1942-3268
KeywordsAlleles, Case-Control Studies, Coronary Disease, Genotype, Group V Phospholipases A2, Humans, Isoenzymes, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide
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.

DOI10.1161/CIRCGENETICS.113.000271
Alternate JournalCirc Cardiovasc Genet
PubMed ID24563418
PubMed Central IDPMC4212409
Grant ListR01 HL-81680 / HL / NHLBI NIH HHS / United States
RG/08/008/25291 / / British Heart Foundation / United Kingdom
G0802432 / / Medical Research Council / United Kingdom
R01 HL036310 / HL / NHLBI NIH HHS / United States
P01 HL-49058 / HL / NHLBI NIH HHS / United States
R01 HL-64035 / HL / NHLBI NIH HHS / United States
G1000143 / / Medical Research Council / United Kingdom
P01 HL-62426 / HL / NHLBI NIH HHS / United States
FS/13/6/29977 / / British Heart Foundation / United Kingdom
RG/10/001/27643 / / British Heart Foundation / United Kingdom
R01 HL-105924 / HL / NHLBI NIH HHS / United States
T32 HL-07692 / HL / NHLBI NIH HHS / United States
G0401527 / / Medical Research Council / United Kingdom
R01 HL-91056 / HL / NHLBI NIH HHS / United States
MR/K006584/1 / / Medical Research Council / United Kingdom
MR/K013351/1 / / Medical Research Council / United Kingdom
P01 HL-077101 / HL / NHLBI NIH HHS / United States
RG/10/12/28456 / / British Heart Foundation / United Kingdom