Association of CYP3A5 Gene Polymorphisms and Amlodipine-Induced Peripheral Edema in Chinese Han Patients with Essential Hypertension

Hao Liang,1,2,* Xinru Zhang,3,* Zhuo Ma,4,* Yan Sun,1,2 Chang Shu,1 Yihua Zhu,5,6 Yanwei Zhang,6 Songnian Hu,1,2 Xiujuan Fu,3 Lihong Liu4 1State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of China; 2University of Chinese Academy of Sciences, Beijing, People’s Republic of China; 3Department of Pharmacy, The Second Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 4Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 5College of Information Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu Province, People’s Republic of China; 6E-Seq Medical Technology Co. Ltd., Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Songnian HuState Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of ChinaTel +86-1064806939Email husn@im.ac.cnLihong LiuDepartment of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of ChinaTel +86-1085231000Email liulihong@bjcyh.comBackground: Amlodipine is one of the most used members of calcium channel blockers (CCB), available to treat hypertension. It is mainly metabolized by the Cytochrome P450 3A4/5 (CYP3A4/5) in the liver. Peripheral edema emerges as the major adverse drug reaction to amlodipine and is the primary reason for discontinuation of amlodipine therapy. However, genetic changes in CYP3A5 may lead to changes in the tolerability of amlodipine.Purpose: In this study, we were interested whether variants in CYP3A5 have a role to play in amlodipine-induced peripheral edema.Methods: A total number of 240 Chinese Han patients that have experienced hypertension were included in the study. Sixty-four patients had experienced amlodipine-induced peripheral edema, while the remaining 176 patients with no history of edema formed the control group. Twenty-four single-nucleotide polymorphisms (SNPs) of CYP3A5 gene were sequenced by targeted region sequencing method. The relationship of these genetic variants with amlodipine-induced peripheral edema risk was assessed using logistic regression.Results: The allele frequencies of CYP3A5*1D (rs15524), CYP3A5*1E (rs4646453) and CYP3A5*3 (rs776746) were significantly different between cases and controls (P< 0.05). The CYP3A5 *3/*3 (CC) or CYP3A5 *1D/*1D (AA) carriers showed an increased risk of amlodipine-induced peripheral edema in dominant model. Meanwhile, patients carrying CYP3A5 *1E (AC/AA) showed a reduced risk of peripheral edema. Furthermore, we found a strong linkage disequilibrium among rs15524, rs4646453 and rs776746.Conclusion: Our study reveals for the first time that CYP3A5 *1D, *1E and *3 were associated with amlodipine-induced peripheral edema in Chinese Han patients with hypertension. However, further studies comprising larger number of samples, more related genes and other factors are wanted.Keywords: pharmacogenomics, amlodipine, edema, CYP3A5, SNP