Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.

Autor: Rotroff DM; Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA.; Department of Statistics, North Carolina State University, Raleigh, North Carolina, USA., Pijut SS; Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, USA., Marvel SW; Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA., Jack JR; Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA., Havener TM; Center for Pharmacogenomics and Individualized Therapy, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA., Pujol A; Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), and CIBERER U759, Center for Biomedical Research on Rare Diseases, Barcelona, Spain.; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain., Schluter A; Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), and CIBERER U759, Center for Biomedical Research on Rare Diseases, Barcelona, Spain., Graf GA; Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, USA.; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, Kentucky, USA.; Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky, USA., Ginsberg HN; Irving Institute for Clinical and Translational Research, Columbia University College of Physicians and Surgeons, New York, New York, USA., Shah HS; Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA., Gao H; Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA., Morieri ML; Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA., Doria A; Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA., Mychaleckyi JC; Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA., McLeod HL; Moffitt Cancer Center, Tampa, Florida, USA., Buse JB; Division of Endocrinology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA., Wagner MJ; Center for Pharmacogenomics and Individualized Therapy, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA., Motsinger-Reif AA; Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA.; Department of Statistics, North Carolina State University, Raleigh, North Carolina, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2018 Apr; Vol. 103 (4), pp. 712-721. Date of Electronic Publication: 2017 Nov 03.
DOI: 10.1002/cpt.798
Abstrakt: 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.
(© 2017 American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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