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=5.1x10(-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.