Pharmacogenetics of dipeptidyl peptidase 4 inhibitors in a Taiwanese population with type 2 diabetes

// Wen-Ling Liao 1, 2, * , Wen-Jane Lee 3, * , Ching-Chu Chen 4, 5, * , Chieh Hsiang Lu 6, 7, 8, * , Chien-Hsiun Chen 5, 9 , Yi-Chun Chou 9 , I-Te Lee 10, 11, 12 , Wayne H-H Sheu 10, 12, 13, 14 , Jer-Yuarn Wu 5, 9 , Chi-Fan Yang 9 , Chung-Hsing Wang 15, 16 , Fuu-Jen Tsai 5, 17, 18 1 Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan 2 Center for Personalized Medicine, China Medical University Hospital, Taichung, Taiwan 3 Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan 4 Division of Endocrinology and Metabolism, Department of Medicine, China Medical University Hospital, Taichung, Taiwan 5 School of Chinese Medicine, China Medical University, Taichung, Taiwan 6 Department of Internal Medicine, Ditmanson Medical Foundation, Chiayi Christian Hospital, Chiayi City, Taiwan 7 Department of Nursing, College of Nursing and Health Sciences, DAYEH University, Changhua, Taiwan 8 Department of Business management, College of Management, National Chung Cheng University, Chia-yi, Taiwan 9 National Center for Genome Medicine, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 10 Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans Hospital, Taichung, Taiwan 11 School of Medicine, Chung Shan Medical University, Taichung, Taiwan 12 School of Medicine, National Yang-Ming University, Taipei, Taiwan 13 School of Medicine, National Defense Medical Center, Taipei, Taiwan 14 Institute of Medical Technology, National Chung-Hsing University, Taichung, Taiwan 15 Department of Genetics and Metabolism, Children’s Hospital of China Medical University, Taichung, Taiwan 16 School of Medicine, China Medical University, Taichung, Taiwan 17 Department of Medical Genetics, China Medical University Hospital, Taichung, Taiwan 18 Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan * These authors have contributed equally to this work Correspondence to: Fuu-Jen Tsai, email: d0704@www.cmuh.org.tw Keywords: DPP-4 inhibitors, pharmacogenetics, Taiwanese, type 2 diabetes Received: January 29, 2016     Accepted: January 03, 2017     Published: February 01, 2017 ABSTRACT Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral anti-hyperglycemic drugs enabling effective glycemic control in type 2 diabetes ( T2D ). Despite DPP-4 inhibitors’ advantages, the patients’ therapeutic response varies. In this retrospective cohort study, 171 Taiwanese patients with T2D were classified as sensitive or resistant to treatment based on the mean change in HbA1c levels. Using an assumption-free genome-wide association study, 45 single nucleotide polymorphisms (SNPs) involved in the therapeutic response to DPP-4 inhibitors ( P < 1 × 10 -4 ) were identified at or near PRKD1 , CNTN3 , ASK, and LOC10537792. A SNP located within the fourth intron of PRKD1 (rs57803087) was strongly associated with DPP-4 inhibitor response ( P = 3.2 × 10 -6 ). This is the first pharmacogenomics study on DPP-4 inhibitor treatment for diabetes in a Taiwanese population. Our data suggest that genes associated with β-cell function and apoptosis are involved in the therapeutic effect of DPP-4 inhibitors, even in the presence of additional oral anti-diabetic drugs. Our findings provide information on how genetic variants influence drug response and may benefit the development of personalized medicine.