Kaixin Zhou

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.

Early genome-wide association studies (GWAS) using relatively small samples have identified both rare and common genetic variants with large impact on severe adverse drug reactions, dosing, and efficacy. Here we outline the challenges and recent successes of the GWAS approach in disease genetics and the ways in which these can be applied to pharmacogenomics for biological discovery, determination of heritability, and personalized treatment. We highlight that the genetic architecture of drug efficacy reflects a complex trait yet that of adverse drug reactions more closely mirrors the architecture of Mendelian diseases and how this difference affects future study design. Given that multiple layers of biological data are increasingly available on large samples from biorepositories linked to electronic medical records, GWAS will remain a key component of the systems biology approach to uncovering small to moderate genetic determinants of drug response; these discoveries should move us closer to a personalized approach to health care.