title: The role of genetic variants in CYP2C8, LPIN1, PPARGC1A and PPARγ on the trough steady-state plasma concentrations of rosiglitazone and on glycosylated haemoglobin A1c in type 2 diabetes.
abstract: OBJECTIVE
  The aim of this study was to examine the effect of single nucleotide polymorphisms in CYP2C8, LPIN1, PPARGC1A and PPARγ on rosiglitazone's (i) trough steady-state plasma concentration (C(ss,min)), (ii) on glycosylated haemoglobin A1c (HbA1c) and (iii) the risk of developing adverse events, mainly oedema, in patients with type 2 diabetes mellitus (T2D).
  
  
  METHODS
  The data used in this study were obtained from the South Danish Diabetes Study including 371 T2D patients with a focus on the 187 patients who were treated with rosiglitazone. The study was a placebo-controlled, partly blinded and multicentre clinical trial. The C(ss,min) of rosiglitazone and HbA1c was determined and the genotype of the patients was identified.
  
  
  RESULTS
  The mean C(ss,min) of rosiglitazone was 21.3 ng/ml (95% confidence interval 18.8; 24.2 ng/ml), with observations ranging from 1 to 296 ng/ml. Carriers of CYP2C8*3 (n=32) (rs10509681 and rs11572080) had a statistically significantly lower mean C(ss,min) than wild types (n=106), and they also had a statistically significantly lower mean absolute difference in HbA1c during rosiglitazone treatment. Finally, the carriers of CYP2C8*3 had a lower odds ratio of developing oedema.
  
  
  CONCLUSIONS
  We showed that CYP2C8*3 was associated with lower plasma levels of rosiglitazone and hence a reduced therapeutic response but also a lower risk of developing oedema during treatment with rosiglitazone. Individualized treatment with rosiglitazone on the basis of the CYP2C8 genotype may therefore be possible.
authors: Department of Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Odense, Denmark. tstage@health.sdu.dk
authors: Tore B
authors: TB
authors: Stage
authors: Mette M H
authors: MM
authors: Christensen
authors: Søren
authors: S
authors: Feddersen
authors: Henning
authors: H
authors: Beck-Nielsen
authors: Kim
authors: K
authors: Brøsen
mesh_terms: D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D054316:Biomarkers, Pharmacological; D065727:Cytochrome P-450 CYP2C8; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D004487:Edema / Q000097:blood / Q000139:chemically induced / Q000150:complications / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006442:Glycated Hemoglobin / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010711:Phosphatidate Phosphatase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D054316:Biomarkers, Pharmacological; D065727:Cytochrome P-450 CYP2C8; D006442:Glycated Hemoglobin; D006360:Heat-Shock Proteins; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010711:Phosphatidate Phosphatase; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D014157:Transcription Factors; C486497:PPARGC1A protein, human; C517652:hemoglobin A1c protein, human; C450259:CYP2C8 protein, human; C485999:LPIN1 protein, human