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

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 =5.1×10 −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.