Abstract P328: Genetic Variants Involved in Postprandial Triglyceride Metabolism are Modified by Fenofibrate Treatment in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study

Abstract

Genetic variants associated with fasting plasma triglycerides (TG) have been reported in the literature. Less is known about genetic variants influencing TG response to dietary factors, specifically a fat challenge (postprandial lipemia, PPL). Additionally, little is known about genetic variants associated with response to pharmacologic agents, such as fenofibrate (FFB), which are used to reduce plasma levels of TG. Preliminary genome-wide association (GWA) analyses on three interventions: 1) FFB; 2) PPL before FFB; and 3) PPL after FFB, implicated different genetic variants associated with the TG response. Therefore, we hypothesized that FFB treatment modifies gene effects on TG response to a dietary postprandial fat challenge. We analyzed participants (N=693) from the GOLDN study who ingested a standardized high-fat meal containing 83% fat and 700 calories/m2 both before and after 3 weeks of daily FFB treatment, thereby having two postprandial plasma TG assessments. Plasma TG was measured at baseline, 3.5 hrs, and 6 hrs after each high-fat meal. The area under the curve (AUC) describing the change in plasma TG concentration over the PPL period was calculated using the trapezoid method. Standardized TG AUC residuals were obtained by using a growth curve method and a stepwise regression approach, retaining covariate terms (age, age2, age3, sex, field center, baseline TG, and principle components (EIGENSTRAT)) that were significant at 5% level. A GWA scan of ∼2.5 million typed or imputed single nucleotide polymorphisms (SNPs) was undertaken to identify gene by FFB treatment interaction effects on the TG AUC PPL response using a repeated measures mixed model with a random effect to adjust for family relatedness. The GWA model included a SNP effect, FFB effect (before or after treatment), and an interaction term (SNP*FFB). For TG AUC residuals, we found GWA significant associations with 8 variants in LDLRAD3 (11p13) for the SNP*FFB term (p<5E-08), and the accompanying main effect terms had suggestive (p<1E-05) associations. These 8 variants are in one linkage disequilibrium block, and indicate that FFB interacts with these variants to decrease their independent effects on TG AUC. In analyses using only the SNP, these 8 variants had p-values <0.005 for TG response to PPL both before and after FFB. SNPs in this group associate with expression of CD44, a molecule which binds osteopontin which is an activator of human adipose tissue macrophages and adipocyte function. This analysis highlights a new gene implicated in TG metabolism whose effect on dietary TG responses to fat ingestion is modified by FFB, possibly by acting through CD44. Further investigation into this gene region is needed in order to enhance our understanding of the underlying mechanistic processes involved in TG metabolism during the postprandial state and the effect of FFB treatment.