OBJECTIVE: Thiazolidinediones (TZDs) are putatively transported into the liver by OATP1B1 (encoded by SLCO1B1) 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 SLCO1B1 521T>C variant was associated with enhanced glycemic response to rosiglitazone (P = 0.04). The super responders defined by combined genotypes at CYP2C8 and SLCO1B1 had a 0.39% (4 mmol/mol) greater HbA1c 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 SLCO1B1 have a large clinical impact on the therapeutic response to rosiglitazone and highlight the importance of studying transporter and metabolizing genes together in pharmacogenetics.
OBJECTIVE:Thiazolidinediones (TZDs) are putatively transported into the liver by OATP1B1 (encoded by SLCO1B1) 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 SLCO1B1 521T>C variant was associated with enhanced glycemic response to rosiglitazone (P = 0.04). The super responders defined by combined genotypes at CYP2C8 and SLCO1B1 had a 0.39% (4 mmol/mol) greater HbA1c 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 SLCO1B1 have a large clinical impact on the therapeutic response to rosiglitazone and highlight the importance of studying transporter and metabolizing genes together in pharmacogenetics.
Authors: Wendy K Chung; Karel Erion; Jose C Florez; Andrew T Hattersley; Marie-France Hivert; Christine G Lee; Mark I McCarthy; John J Nolan; Jill M Norris; Ewan R Pearson; Louis Philipson; Allison T McElvaine; William T Cefalu; Stephen S Rich; Paul W Franks Journal: Diabetologia Date: 2020-09 Impact factor: 10.122
Authors: John J Nolan; Anna R Kahkoska; Zhila Semnani-Azad; Marie-France Hivert; Linong Ji; Viswanathan Mohan; Robert H Eckel; Louis H Philipson; Stephen S Rich; Chandra Gruber; Paul W Franks Journal: Diabetes Care Date: 2022-02-01 Impact factor: 19.112
Authors: John M Dennis; William E Henley; Michael N Weedon; Mike Lonergan; Lauren R Rodgers; Angus G Jones; William T Hamilton; Naveed Sattar; Salim Janmohamed; Rury R Holman; Ewan R Pearson; Beverley M Shields; Andrew T Hattersley Journal: Diabetes Care Date: 2018-08-02 Impact factor: 19.112