Type II Secretory Phospholipase A2 and Prognosis in Patients with Stable Coronary Heart Disease: Mendelian Randomization Study

Background Serum type II secretory phospholipase A 2 (sPLA 2 -IIa) has been found to be predictive of adverse outcomes in patients with stable coronary heart disease. Compounds targeting sPLA 2 -IIa are already under development. This study investigated if an association of sPLA 2 -IIa with secondary cardiovascular disease (CVD) events may be of causal nature or mainly a matter of confounding by correlated cardiovascular risk markers. Methodology/Principal Findings Eight-year follow-up data of a prospective cohort study (KAROLA) of patients who underwent in-patient rehabilitation after an acute cardiovascular event were analysed. Associations of polymorphisms (SNP) in the sPLA 2 -IIa-coding gene PLA2G2A with serum sPLA 2 -IIa and secondary fatal or non-fatal CVD events were examined by multiple regression. Hazard ratios (HR) were compared with those expected if the association between sPLA 2 -IIa and CVD were causal. The strongest determinants of sPLA 2 -IIa (rs4744 and rs10732279) were associated with an increase of serum concentrations by 81% and 73% per variant allele. HRs (95% confidence intervals) estimating the associations of the SNPs with secondary CVD events were increased, but not statistically significant (1.16 [0.89–1.51] and 1.18 [0.91–1.52] per variant allele, respectively). However, these estimates were very similar to those expected when assuming causality (1.18 and 1.17), based on an association of natural log-transformed sPLA 2 -IIa concentration with secondary events with HR = 1.33 per unit. Conclusion The present findings regarding genetic polymorphisms, determination of serum sPLA 2 -IIa, and prognosis in CVD patients are consistent with a genuine causal relationship and thus might point to a valid drug target for prevention of secondary CVD events.