Rare LPL gene variants attenuate triglyceride reduction and HDL cholesterol increase in response to fenofibric acid therapy in individuals with mixed dyslipidemia

Objective: Individuals with mixed dyslipidemia have elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and increased risk for coronary disease. Fibrate therapy is commonly used to lower TG and increase HDL-C. Common genetic variants are known to affect the response to fibrate therapy. We sought to identify rare genetic variants (frequency≤1%) in genes involved in TG and HDL-C metabolism that affect the response to fenofibric acid (FA) therapy. Methods: Four genes with a major role in HDL-C and TG metabolism APOA1, APOC2, APOC-III and LPL were sequenced in 2385 participants with mixed dyslipidemia in a randomized, double-blind, active-controlled study comparing therapy with FA alone, in combination with statins, or statin alone. Rare variants collapsing or SKAT methods were used for the analysis. Results: Synonymous rare variants in the LPL gene were significantly associated with absolute HDL-C change (P=9×10^-4) and TG percent change (P=6.76×10^-4) in those treated with FA only. Participants with these rare variants had a 2mg/dL increase in HDL-C and 39mg/dL decrease in TG as compared to 6.2mg/dL increase in HDL-C and 100mg/dL decrease in TG in those without these variants. Rare variants in the APOC-III gene were associated with a modest 3mg/dL less reduction in APOB (P=8.72×10^-4) in those receiving FA and statin. Conclusion: In individuals with mixed dyslipidemia rare synonymous variants within LPL gene were associated with attenuated response to FA therapy while APOCIII rare variants were associated with a modest effect on APOB response to FA-statin therapy. These results should be replicated in a similar clinical trial for further confirmation.