Abstract 908: In Vivo Role of the Pharmacogenetics of Glucuronidation in the Disposition and Triglyceride Response to Fenofibrate
In spite of optimal low-density lipoprotein (LDL-C) lowering with statins, cardiovascular risk remains high for patients with elevated triglyceride (TG)-low high-density cholesterol (HDL-C) profiles. Fenofibric acid, the active moiety of fenofibrate, acts on the peroxisome proliferator-activated nuclear receptor-alpha (PPAR-α) to lower TG and raise HDL-C. The extent of lipid response has been shown to be associated with serum concentrations (conc.) of fenofibric acid. In vitro work confirms fenofibric acid is primarily eliminated by UDP-glucuronosyltransferases (UGTs) including UGT2B7, and others (UGT1A1, UGT1A3 and UGT1A9). Therefore, we hypothesized genetic variations in UGT activity may be associated with fenofibric acid conc. and thus may influence lipid response.
Purpose: To test if the A-327G SNP (rs7662029) for UGT2B7, which has been shown to modulate UGT2B7 expression in vitro, is associated with serum conc. of fenofibric acid and TG response in vivo.
Methods: As part of the NHLBI sponsored Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, participants providing consent and not currently taking lipid lowering medications, were analyzed for fasting lipid response pre and post 21 days of once daily 160mg fenofibrate. TG response was calculated by the log of the ratio of the average of the 2 pre- and post-fenofibrate exposure TG determinations. Associations between UGT2B7 A-327G genotype and steady-state trough fenofibric acid conc. as well as TG response were analyzed by linear regression.
Results: 745 participants (51% male) with both genotype and phenotype data 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). The G allele frequency for UGT2B7A>G was 0.49 and was in HWE (p = 0.8). After adjusting for age, age2, sex, alcohol use, height and serum creatinine, strong associations were observed between UGT2B7 A-327G genotypes and steady-state trough fenofibric acid conc. (log-transformed, p = 4 × 10−8) as well as TG response (p = 0.002, also adjusted for baseline TG).
Conclusion: This study suggests UGT2B7 A-327G genotype may contribute to TG response by way of influencing glucuronidation activity of fenofibric acid.