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.