Abstract 16838: Genetics of Insulin Response to Fenofibrate in the Goldn Study
Background: Fenofibrate is an effective treatment for hypertriglyceridemia but also improves cholesterol levels, markers of inflammation, and insulin resistance. Fenofibrate binds to the transcription factor peroxisome proliferator-activated receptor-α (PPARα) which regulates expression of a number of genes. How fenofibrate improves measures of insulin resistance is not completely understood. We sought to determine whether there are genes that influence the effect of fenofibrate on measures of insulin resistance.
Methods: We performed a genome wide association study (GWAS) of change in fasting insulin after fenofibrate treatment in the Genetics of Lipid Lowering and Diet Network (GOLDN) study. We calculated change in fasting insulin concentration among 750 GOLDN participants without diabetes that were treated with fenofibrate (160 mg/day) for 3 weeks. Genotyping was done with Affymetrix Human SNP Array 6.0. Of one million SNPs genotyped, 718, 542 met the genotype quality control criteria and were tested for association with change in fasting insulin. Genetic variants were modeled using multivariable linear regression models adjusting for age, sex, center, and family relationship.
Results: The three most statistically significant loci were near inositol 1,4,5-triphosphate receptor, type 2 (ITPR2, rs16930147, P=2.6*10-7), monooxygenase DBH-like 1 isoform 2 (MOXD1, rs7751860, P=1.3*10-6) and chromatin modifying protein 4C (CHMP4C, rs11996762, P=1.4*10-6). ITPR2 has been associated with waist-to-hip ratio and is highly expressed in human adipocytes. MOXD1 has been shown to be upregulated in the livers of transgenic mice with reduced bioavailability of insulin. Finally, CHMP4C has been implicated in p53 regulation of the endosomal compartment in response to stress where the endosome plays a major role in intracellular cholesterol metabolism.
Conclusions: The results show novel loci that may play a role in insulin response to fenofibrate treatment, and can shed light on the pathways underlying this treatment benefit which can help reduce cardiovascular disease risk in treated patients.
- © 2011 by American Heart Association, Inc.