Type II secretory phospholipase a 2 and prognosis in patients with stable coronary heart disease: Mendelian randomization study

Abstract

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. © 2011 Breitling et al.