Abstract 141: APOA1, CETP, and CILP2 Variants Modify the Lipid Response to Fenofibrate: Genetics of Lipid Lowering and Diet Network
Introduction: Despite the widespread use of fibrates in treatment of dyslipidemia, the observed response is highly heterogeneous, suggesting a role for genetic determinants. Whether replicated variants associated with blood lipids identified by genome wide association studies (GWAS) are also associated with lipid response to fenofibrate is unknown.
Objectives: To test if 95 genome-wide significant loci identified in a recent meta-analysis of blood lipids are associated with changes in high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, and triglycerides (TG) following 3 weeks of therapy with 160 mg of micronized fenofibrate.
Methods: Using data from 861 European American Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) participants, we fit mixed linear models with baseline blood lipids and the post-to-pre fenofibrate treatment ratio of blood lipid levels as outcomes, the corresponding genetic markers from the published meta-analysis as predictors, and age, sex, pedigree, and ancestry as assessed by principal components as covariates. A Bonferroni correction was applied to adjust for multiple comparisons. Least square means were used to report the direction of fenofibrate-induced changes by genotype.
Results: We observed statistically significant associations between rs964184, a variant near the APOA1 gene, and baseline HDL-C (P<0.0001) and baseline TG (P<0.0001), as well as with diminished response to fenofibrate as evidenced by a smaller increase in HDL-C (P<0.0001) and a smaller decrease in TG (P=0.0001) per each copy of the variant allele. Additionally, we report suggestive associations of rs3764261 locus in the CETP gene and the rs10401969 locus in the CILP2 gene with decreased fenofibrate response as measured by changes in LDL-C (P=0.0003 and 0.02, respectively) and non-HDL-C (P=0.004 and 0.005, respectively).
Conclusions: We have identified several novel biologically relevant loci associated with baseline blood lipids and fenofibrate-induced changes in blood lipids.
- © 2012 by American Heart Association, Inc.