Regular article Systematic characterization and comparison of the CYP2C9 variability of the Orang Asli in Malaysia with 12 populations Q4 Lay Kek Teh a, b, * , Vinothini Subramaniam a , Tuan Azlin Tuan Abdu Aziz a , Lian Shien Lee a , Mohamed Izwan Ismail a , Choo Yee Yu a , Geik Yong Ang a , Mohammad Richard James Johari a, b , Rose Iszati Ismet a , Noor Saadah Sahak a , Aminuddin Ahmad c , Thuhairah Abdul Rahman c , Fadzilah Mohd Nor @ Ghazali c , SyahrulAzlin Shaari c , Mustaffa Omar d , Adzrool Idzwan Ismail e , Kamarudzaman Md. Isa f , Hood Salleh d, g , Mohd Zaki Salleh a, b, * a Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM), Malaysia b Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Malaysia c Faculty of Medicine, Universiti Teknologi MARA (UiTM), Malaysia d Faculty of Social Sciences and Humanities, Universiti Kebangsaan Malaysia (UKM), Malaysia e Faculty of Art and Design (FSSR), Universiti Teknologi MARA (UiTM), Malaysia f Faculty of Communication and Media, University Selangor (Unisel), Malaysia g Institut Alam Sekitar dan Pembangunan (LESTARI), Universiti Kebangsaan Malaysia (UKM), Malaysia article info Article history: Received 2 March 2016 Received in revised form 4 April 2016 Accepted 20 April 2016 Available online xxx Keywords: Genetic polymorphism Interethnic Hardy Weinberg Equilibrium Orang Asli Malaysia abstract We conducted a systematic characterization of CYP2C9 variants in 61 Orang Asli and 96 Singaporean Malays using the whole genome sequences data and compared the variants with the other 11 HapMap populations. The frequency of rs1057910 (CYP2C9*3) is the highest in the Orang Asli compared to other populations. Three alleles with clinical implication were detected in the Orang Asli while 2 were found in the Singaporean Malays. Large numbers of the Orang Asli are predicted to have reduced metabolic ca- pacity and therefore they would require a lower dose of drugs which are metabolized by CYP2C9. They are also at increased risks of adverse effects and therapeutic failures. A large number of CYP2C9 variants in the Orang Asli were not in the Hardy Weinberg Equilibrium which could be due to small sample size or mutations that disrupt the equilibrium of allele frequencies. In conclusion, different polymorphism patterns, allele frequencies, genotype frequencies and LD blocks are observed between the Orang Asli, the Singaporean Malays and the other populations. The study provided new information on the genetic polymorphism of CYP2C9 which is important for the implementation of precision medicine for the Orang Asli Q1 . © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved. 1. Introduction CYP2C9 is one of the important cytochrome P450 enzymes that metabolizes not only xenobiotics but also endogenous compounds such as arachidonic acid, 5-hydroxytryptamine, and linoleic acid [1]. Therapeutic agents that are substrates of CYP2C9 include warfarin, phenytoin, tolbutamide, losartan, glipizide and some nons Q5 teroidal anti-inflammatory drugs [2]. Differences in the metabolic activities of the CYP2C9 had been reported to result in different drug responses; from therapeutic failure due to toxicity or insufficient dose to desired therapeutics efficacy. Diminished metabolic capacity of Cytochrome p450 enzymes because of ge- netic polymorphisms or drugedrug interactions can lead to toxic- ities at normal therapeutic doses [3,4]. Studies have successfully associated CYP2C9 variants, rs1799853 (CYP2C9*2) and rs1057910 (CYP2C9*3) with poor metabolism phe- notypes. Patients with these variants require lower doses of warfarin as they are at risks of prolonged bleeding time and increased incidence of severe bleeding [5e8]. Carriers of these variants were also associated with an increased risk of * Corresponding authors. E-mail addresses: tehlaykek2016@gmail.com, tehlaykek@gmail.com (L.K. Teh), zakisalleh.mzs@gmail.com (M.Z. Salleh). Contents lists available at ScienceDirect Drug Metabolism and Pharmacokinetics journal homepage: http://www.journals.elsevier.com/drug-metabolism-and- pharmacokinetics http://dx.doi.org/10.1016/j.dmpk.2016.04.004 1347-4367/© 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved. Drug Metabolism and Pharmacokinetics xxx (2016) 1e10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 DMPK109_proof ■ 4 May 2016 ■ 1/10 Please cite this article in press as: Teh LK, et al., Systematic characterization and comparison of the CYP2C9 variability of the Orang Asli in Malaysia with 12 populations, Drug Metabolism and Pharmacokinetics (2016), http://dx.doi.org/10.1016/j.dmpk.2016.04.004