Abstract
Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10 -6 ). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor-beta (TGF-β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D.
| Original language | English |
|---|---|
| Pages (from-to) | 712-721 |
| Number of pages | 10 |
| Journal | Clinical Pharmacology and Therapeutics |
| Volume | 103 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2018 |
Bibliographical note
Funding Information:This research was supported by a National Heart, Lung, and Blood Institute grant to the University of North Carolina at Chapel Hill (5R01HL110380-04) and R01 HL110400 to the Joslin Diabetes Center and the University of Virginia. Dr Ginsberg received support from National Heart, Lung, and Blood Institute R01 HL110418.
Publisher Copyright:
© 2017 American Society for Clinical Pharmacology and Therapeutics
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)
