Association of PLA2G4A with myocardial infarction is modulated by dietary PUFAs

Background: Leukotrienes are proinflammatory molecules derived from dietary PUFAs and have been associated with cardiovascular disease (CVD). We previously reported that an A→G variant (rs12746200) of the cytosolic phospholipase A2 group IVA gene (PLA2G4A), which encodes the enzyme that liberates PUFAs from cellular membranes for leukotriene synthesis, decreases the risk of CVD. Objective: We sought to replicate these initial observations with a more clinically relevant phenotype, such as myocardial infarction (MI), and to determine whether dietary PUFAs mediate this association. Design: In a Costa Rican case-control data set (n = 3971), rs12746200 was genotyped and was tested for an association with MI. Functional experiments were carried out to determine whether rs12746200 led to differences in mRNA expression. Results: Risk of MI was significantly lower in AG/GG subjects than in AA homozygotes (OR: 0.86; 95% CI: 0.75, 0.99; P = 0.040). The reduced risk of MI was observed primarily in AG/GG subjects who were above the median for intake of dietary omega-6 (n−6) PUFAs (OR: 0.71; 95% CI: 0.59, 0.87; P-interaction = 0.005). A similar analysis with dietary omega-3 (n−3) PUFAs did not show a statistically significant nutrigenetic association (P-interaction = 0.23). Functional analysis in human aortic endothelial cells showed that the carriers of the G allele had significantly lower PLA2G4A gene expression (P = 0.014), consistent with the atheroprotective association of this variant. Conclusion: These results replicate the association of rs12746200 with CVD phenotypes and provide evidence that the protective association of this functional PLA2G4A variant is mediated by dietary PUFAs.