Joint effects of diabetic-related genomic loci on the therapeutic efficacy of oral anti-diabetic drugs in Chinese type 2 diabetes patients

Previous pharmacogenomic studies of oral anti-diabetic drugs have primarily focused on the effect of a single site. This study aimed to examine the joint effects of multiple loci on repaglinide or rosiglitazone efficacy in newly diagnosed type 2 diabetes mellitus (T2DM) patients. A total of 209 newly diagnosed T2DM patients were randomly assigned to treatment with repaglinide or rosiglitazone for 48 weeks. The reductions in fasting glucose (ΔFPG), 2h glucose (Δ2hPG) and glycated hemoglobin (ΔHbA1c) levels were significantly associated with genetic score that was constructed using the sum of the effect alleles both in the repaglinide (P = 0.0011, 0.0002 and 0.0067, respectively) and rosiglitazone cohorts (P = 0.0002, 0.0014 and 0.0164, respectively) after adjusting for age, gender, body mass index and dosage. Survival analyses showed a trend towards a greater attainment rate of target HbA1c level in individuals with a high genetic score in the repaglinide cohort and rosiglitazone cohort (P(log-rank) = 0.0815 and 0.0867, respectively) when the attainment of treatment targets were defined as more than 20% decrease of FPG, 2hPG, and HbA1c levels after treatment. In conclusion, we identified the joint effects of several T2DM-related loci on the efficacy of oral anti-diabetic drugs; moreover, we built a model to predict the drug efficacy.