TY - JOUR
T1 - Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes
AU - Rotroff, Daniel M.
AU - Pijut, Sonja S.
AU - Marvel, Skylar W.
AU - Jack, John R.
AU - Havener, Tammy M.
AU - Pujol, Aurora
AU - Schluter, Agatha
AU - Graf, Gregory A.
AU - Ginsberg, Henry N.
AU - Shah, Hetal S.
AU - Gao, He
AU - Morieri, Mario Luca
AU - Doria, Alessandro
AU - Mychaleckyi, Josyf C.
AU - McLeod, Howard L.
AU - Buse, John B.
AU - Wagner, Michael J.
AU - Motsinger-Reif, Alison A.
N1 - Publisher Copyright:
© 2017 American Society for Clinical Pharmacology and Therapeutics
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
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U2 - 10.1002/cpt.798
DO - 10.1002/cpt.798
M3 - Article
C2 - 28736931
AN - SCOPUS:85032957568
SN - 0009-9236
VL - 103
SP - 712
EP - 721
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 4
ER -