Abstract 1442: Pharmacogenetics and the Role of UGT2B7 in the Disposition and Triglyceride Response to Fenofibrate
Serum triglycerides (TG) remain an important predictor of coronary heart disease even for patients treated with statins. Fenofibric acid, the active moiety of fenofibrate, lowers TGs and raises high density cholesterol (HDL-C). Lipid response is associated with serum concentration (conc.) of fenofibric acid which is eliminated by UDP-glucuronosyltransferases (UGTs). Variability in lipid response to fenofibrate is considerable yet sources of this variability are poorly understood.
Purpose: To better understand the contribution of UGTs to fenofibrate’s response variability, we examined the association between 11 UGT2B7 SNPs, and both serum conc. of fenofibric acid and TG response.
Methods: As part of the NHLBI sponsored Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, participants not taking lipid lowering medications were analyzed for fasting lipid profiles pre and post 21 days of once daily 160mg fenofibrate. TG response was calculated as log of the post- over pre-fenofibrate TG values. Genotype associations with steady-state trough fenofibric acid conc. and TG response were analyzed by mixed effects linear regression adjusting for age, sex, alcohol use, smoking, BMI, study center and serum creatinine, and pre-fenofibrate TG (for TG response only).
Results: 861 participants (51% male) were included. The mean (SD) age was 49 (16) years and the median (25th,75th percentile) % change in TG concentrations was −32.3 (−45.2, −19.0). No SNPs deviated from HWE. Significant associations with fenofibric acid conc. were observed for 5 SNPs: A-327G, C2099T, A869C, C8853G and C10224T. The p-values ranged from 0.000003 to 0.028. A significant association with TG response with only UGT2B7 A-327G (rs7662029) remained significant (p=0.0001) after adjusting for the other 4 SNPs. The G allele for the promoter A-327G is associated with greater TG lowering response.
Conclusion: This study suggests several UGT2B7 SNPs contribute independently to serum fenofibric acid concentrations. We conclude that UGT2B7 contributes to the TG response variability of fenofibrate by influencing glucuronidation of fenofibric acid.