CYP2C8 and SLCO1B1 Variants and Therapeutic Response to Thiazolidinediones in Patients With Type 2 Diabetes.
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.



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.



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 HbA1creduction (P = 0.006) than the poor responders. Neither of the variants had a significant impact on pioglitazone response.



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.
Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, Scotland.
Adem Y
AY
Dawed
Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, Scotland.
Louise
L
Donnelly
Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, Scotland.
Roger
R
Tavendale
Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, Scotland.
Fiona
F
Carr
Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, Scotland.
Graham
G
Leese
Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, Scotland.
Colin N A
CN
Palmer
Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, Scotland.
Ewan R
ER
Pearson
Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, Scotland k.zhou@dundee.ac.uk.
Kaixin
K
Zhou
D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D016014:Linear Models; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D000077205:Pioglitazone; D020641:Polymorphism, Single Nucleotide; D000077154:Rosiglitazone; D012606:Scotland; D045162:Thiazolidinediones / Q000627:therapeutic use*; D016896:Treatment Outcome; D044465:White People / Q000235:genetics
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; C503999:SLCO1B1 protein, human; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D000077205:Pioglitazone