Pharmacogenomics Studies Of Oral Antidiabetic Drugs In Chinese Patients With Type 2 Diabetes

Pharmacogenomics studies which focus on the role of genetic factors in the variability of drug response could help find out genetic marks and offer guidence for personal medicine.We focused on oral antidiabetic drugs repaglinide and rosiglitazone,and carried out pharmacogenmics studies in Chinese type 2 diabetic patients.The contents and main findings are as follows:We investigate the association of PAX4 variants?rs6367136 and rs10229583?and PSMD6 variant rs831571 with therapeutic efficacy of repaglinide and rosiglitazone in Chinese type 2diabtes mellitus?T2DM?patients.A total of 209 newly diagnosed T2DM patients were randomly assigned to treatment with repaglinide or rosiglitazone for 48 weeks,and the therapeutic effects were compared.The results showed that PAX4 variant rs6467136 was associated with the therapeutic efficacy of rosiglitazone.GA and AA carriers showed greater decrease in 2h glucose?2hPG?levels?P=0.0063?and higher cumulative attainment rates of target 2hPG levels(P_logrank=0.0093)than GG homozygotes.PSMD6 rs831671 was associated with the therapeutic efficacy of repaglinide and rosiglitazone.In the rosiglitazone cohort,rs831571 showed significant associations with FPG,2hPG and decrement of glycated haemoglobin?HbA1c?levels after 24 weeks of treatment?P=0.0368,0.0468 and 0.0247,respectively?.In the repaglinide cohort,rs831571 was significantly associated with decreased HbA1c levels after 24 weeks of treatment and HOMA-IR after 48 weeks of treatment with repaglinide?P=0.0096 and 0235,respectively?.Therefore,we found PAX4 and PSMD6 variants were associated with the therapeutic efficacy of repaglinide and rosiglitazone in Chinese type 2 diabetes patients.In addition,we genotyped the CYP2C8*3,CYP3A4*18 and CYP2C9*3 in newly diagnosed type 2diabetes patients,and found these variants were not associated with the therapeutic efficacy of repaglinide and rosiglitazone.Finally,we examine the joint effects of multiple loci on repaglinide or rosiglitazone efficacy in newly diagnosed T2DM patients.The reductions in fasting glucose??FPG?,2h glucose??2hPG?and glycated hemoglobin??HbA1c?levels were significantly associated with genetic score that was constructed using the sum of the effect alleles both in the rosiglitazone?P=<0.001,0.0004 and 0.0057,respectively?and repaglinide cohorts?P=<0.001,0.0005 and 0.0008,respectively?after adjusting for age,gender,body mass index and dosage.Therefore,we identified the joint effects of mutiple loci on the efficacy of oral anti-diabetic drugs;moreover,we built a model to predict the drug efficacy.