Polyunsaturated Fatty Acids Interact with the PPARA-L162V Polymorphism to Affect Plasma Triglyceride and Apolipoprotein C-III Concentrations in the Framingham Heart Study

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear transcription factor regulating multiple genes involved in lipid metabolism. It was shown that a common leucine to valine (L162V) substitution at the PPARalpha gene (PPARA) is functional and affects transactivation activity of PPARalpha ligands, such as PUFA, on a concentration-dependent basis. The current study examined this gene-nutrient interaction in relation to plasma lipid variables in a population-based study consisting of 1003 men and 1103 women participating in the Framingham cohort and consuming their habitual diets. We found significant gene-nutrient interactions between the L162V polymorphism and total PUFA intake, which modulated plasma triglycerides (TG; P < 0.05) and apolipoprotein C-III (apoC-III; P < 0.05) concentrations. The 162V allele was associated with greater TG and apoC-III concentrations only in subjects consuming a low-PUFA diet (below the population mean, 6% of energy). However, when PUFA intake was high, carriers of the 162V allele had lower apoC-III concentrations. This interaction was significant even when PUFA intake was considered as a continuous variable (P = 0.031 for TG and P < 0.001 for apoC-III), suggesting a strong dose-response effect. When PUFA intake was <4%, 162V allele carriers had approximately 28% higher plasma TG than did 162L homozygotes (P < 0.01). Conversely, when PUFA intake was >8%, plasma TG in 162V allele carriers was 4% lower than in 162L homozygotes. Similar results were obtained for (n-6) and (n-3) fatty acids. Our data show that the effect of the L162V polymorphism on plasma TG and apoC-III concentrations depends on the dietary PUFA, with a high intake triggering lower TG in carriers of the 162V allele.