期刊
DIABETES CARE
卷 39, 期 11, 页码 1902-1908出版社
AMER DIABETES ASSOC
DOI: 10.2337/dc15-2464
关键词
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资金
- Wellcome Trust [102820/Z/13/Z]
- Diabetes UK [10/0004063]
- Sir Henry Wellcome postdoctoral fellowship [092272/Z/10/Z]
- Wellcome Trust [092272/Z/10/Z] Funding Source: Wellcome Trust
OBJECTIVE Thiazolidinediones (TZDs) are putatively transported into the liver by OATP1B1 (encoded by SLC0181) and metabolized by CYP450 2C8 enzyme (encoded by CYP2C8). While CYP2C8*3 has been shown to alter TZD pharmacokinetics, it has not been shown to alter efficacy. RESEARCH DESIGN AND METHODS We genotyped 833 Scottish patients with type 2 diabetes treated with pioglitazone or rosiglitazone and jointly investigated association of variants in these two genes with therapeutic outcome. RESULTS The CYP2C8*3 variant was associated with reduced glycemic response to rosiglitazone (P = 0.01) and less weight gain (P = 0.02). The SLC0181 521T>C variant was associated with enhanced glycemic response to rosiglitazone (P = 0.04). The super responders defined by combined genotypes at CYP2C8 and SLC0181 had a 0.39% (4 mmol/mol) greater HbAi, reduction (P = 0.006) than the poor responders. Neither of the variants had a significant impact on pioglitazone response. CONCLUSIONS These results show that variants in CYP2C8 and SLC0181 have a large clinical impact on the therapeutic response to rosiglitazone and highlight the importance of studying transporter and metabolizing genes together in pharmacogenetics.
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