The genetic architecture of fasting plasma triglyceride response to fenofibrate treatment

Abstract

Metabolic response to the triglyceride (TG)-lowering drug, fenofibrate, is shaped by interactions between genetic and environmental factors, yet knowledge regarding the genetic determinants of this response is primarily limited to single-gene effects. Since very low-density lipoprotein (VLDL) is the central carrier of fasting TG, identifying factors that affect both total TG and VLDL -TG response to fenofibrate is critical for predicting individual fenofibrate response. As part of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, 688 individuals from 161 families were genotyped for 91 single-nucleotide polymorphisms (SNPs) in 25 genes known to be involved in lipoprotein metabolism. Using generalized estimating equations to control for family structure, we performed linear modeling to investigate whether single SNPs, single covariates, SNP -SNP interactions, and/or SNP -covariate interactions had a significant association with the change in total fasting TG and fasting VLDL -TG after 3 weeks of fenofibrate treatment. A 10-iteration fourfold cross-validation procedure was used to validate significant associations and quantify their predictive abilities. More than one-third of the significant, cross-validated SNP -SNP interactions predicting each outcome involved just five SNPs, showing that these SNPs are of key importance to fenofibrate response. Multiple variable models constructed using the top-ranked SNPcovariate interactions explained 11.9% more variation in the change in TG and 7.8% more variation in the change in VLDL than baseline TG alone. These results yield insight into the complex biology of fenofibrate response, which can be used to target fenofibrate therapy to individuals who are most likely to benefit from the drug.

Association between glucokinase regulatory protein (GCKR) and apolipoprotein A5 (APOA5) gene polymorphisms and triacylglycerol concentrations in fasting, postprandial, and fenofibrate-treated states

“…Fibrates stimulate cellular fatty acid uptake, conversion to acyl-CoA derivatives, and catabolism by the beta-oxidation pathways, which, combined with a reduction in fatty acid and triacylglycerol synthesis, results in a decrease in VLDL production. It has been shown that interindividual variations in the response to fenofibrate could be partially driven by genetic factors (31,32). In this regard, our study shows that the fenofibrate-induced reduction of triacylglycerol concentrations was more evident in subjects within the higher risk group (R) than in those in the intermediate (M) and protective (P) genotype groups.…”

Fenofibrate and Metabolic Syndrome

“…Smith et al [93], for example, with the GOLDN study data reported 4 SNPs ( APOA4_M35, APOC3_3U386, ABCA1_I27943 , and LIPC_T224T ) responsible for a large portion of the SNP-covariate interaction that predicted the TG change. Different from previous studies, we performed multivariate factor analysis and random coefficients growth curves on the repeated measures.…”

A family-specific linkage analysis of blood lipid response to fenofibrate in the Genetics of Lipid Lowering Drug and Diet Network

“…However, known genetic factors only account for a modest proportion of inherited heterogeneity in treatment response (1), highlighting the need for cost-effective identification of novel, especially rare, pharmacogenetic variants. Previous simulations have shown that family-specific linkage analysis provides a powerful way to select samples that carry rare alleles, even when the aggregate evidence of linkage is weak (2).…”