A Two-Stage Study Identifies Two Novel Polymorphisms in PRKAG2 Affecting Metformin Response in Chinese Type 2 Diabetes Patients

Di Xiao,1,2,* Jun-Yan Liu,3,* Si-Min Zhang,4,* Rang-Ru Liu,1,5 Ji-Ye Yin,1,6 Xue-Yao Han,4 Xi Li,1,6 Wei Zhang,1,6,7 Xiao-Ping Chen,1,6 Hong-Hao Zhou,1,6,7 Li-Nong Ji,4 Zhao-Qian Liu1,6,7 1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Department of pharmacy, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Department of orthopaedics, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4Department of Endocrinology and Metabolism, The People’s Hospital of Peking University, Beijing, People’s Republic of China; 5Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education & Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, People’s Republic of China; 6Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, People’s Republic of China; 7National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhao-Qian Liu; Li-Nong Ji Email liuzhaoqian63@126.com; jiln@gmail.comObjective: Individual differences in glycemic response to metformin in antidiabetic treatment exist widely. Although some associated genetic variations have been discovered, they still cannot accurately predict metformin response. In the current study, we set out to investigate novel genetic variants affecting metformin response in Chinese type 2 diabetes (T2D) patients.Methods: A two-stage study enrolled 500 T2D patients who received metformin, glibenclamide or a combination of both were recruited from 2009 to 2012 in China. Change of HbA1c, adjusted by clinical covariates, was used to evaluate glycemic response to metformin. Selected single nucleotide polymorphisms (SNPs) were genotyped using the Infinium iSelect and/or Illumina GoldenGate genotyping platform. A linear regression model was used to evaluate the association between SNPs and response.Results: A total of 3739 SNPs were screened in Stage 1, of which 50 were associated with drug response. Except for one genetic variant preferred to affect glibenclamide, the remaining SNPs were subsequently verified in Stage 2, and two SNPs were successfully validated. These were PRKAG2 rs2727528 (discovery group: β=− 0.212, P=0.046; validation group: β=− 0.269, P=0.028) and PRKAG2 rs1105842 (discovery group: β=0.205, P=0.048; validation group: β=0.273, P=0.025). C allele carriers of rs2727528 and C allele carriers of rs1105842 would have a larger difference of HbA1c level when using metformin.Conclusion: Two variants rs2727528 and rs1105842 in PRKAG2, encoding γ 2 subunit of AMP-activated protein kinase (AMPK), were found to be associated with metformin response in Chinese T2D patients. These findings may provide some novel information for personalized pharmacotherapy of metformin in China.Keywords: type 2 diabetes, metformin response, genetic variants, PRKAG2