Abstract
Genetic variations in CYP2C9 are associated to inter-individual variability of drugs metabolism and response. The only report has been done previously mainly focusing on the common variant alleles of CYP2C9 in Vietnamese Kinh subjects. However, little is known about the complete spectrum of this gene polymorphism in different ethnic groups of Vietnam. We sequenced the promoter region and all exons of CYP2C9 in 100 healthy unrelated Vietnamese Kinh subjects. Additionally, common CYP2C9 variants, *2 and *3, were also analyzed by RFLP-PCR in extra 194 Kinh subjects and 279 of other four ethnic groups in Vietnam. The results of these common variants observed from five ethnic groups were compared with other populations in the world. Seven previously reported alleles and two genotypes were determined in Kinh subjects. The percentage of CYP2C9*1 and CYP2C9*3 alleles are 96.5 and 3.5%, respectively. We found one novel non-synonymous variant in exon 7 leading to amino acid change at 363 position from proline to histidine. Functional analysis by SIFT and Polyphen-2 indicated that this mutation is intolerant and probably damaging. Prevalence of CYP2C9*2 observed in Vietnamese population was significantly lower compared with that of other populations in the South and West of Asia as well as in Europe. This study provides information of genetic distribution pattern of CYP2C9 in Vietnamese, which would be useful for optimizing drug therapies in Vietnam.
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Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T (1992) Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin—drug interactions. Chem Res Toxicol 5:54–59
Bajpai M, Roskos LK, Shen DD, Levy RH (1996) Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite. Drug Metab Dispos 24(12):1401–1403
Stearns RA, Chakravarty PK, Chen R, Chiu SH (1995) Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Role of cytochrome P4502C and 3A subfamily members. Drug Metab Dispos 23(2):207
Tracy TS, Rosenbluth BW, Wrighton SA, Gonzalez FJ, Korzekwa KR (1995) Role of cytochrome P450 2C9 and an allelic variant in the 4′-hydroxylation of (R)- and (S)-flurbiprofen. Biochem Pharmacol 49(9):1269–1275
Hamman MA, Thompson GA, Hall SD (1997) Regioselective and stereoselective metabolism of ibuprofen by human cytochrome P450 2C. Biochem Pharmacol 54(1):33–41
Kurose K, Sugiyama E, Saito Y (2012) Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab Pharmacokinet 27(1):9–54
Jin T, Xun X, Du S, Geng T, Wang H, Feng T, Chen C, Yuan D, Kang L (2016) Genetic polymorphisms analysis of drug-metabolizing enzyme CYP2C9 in the Uyghur population. Xenobiotica 46(8):709–714
Adzhubei I, Jordan DM, Sunyaev SR (2013) Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet 7:7.20
Pauline CN, Steven H (2006) Predicting the Effects of Amino Acid Substitutions on Protein Function. Annu Rev Genomics Hum Genet 7:61–80
Lee SS, Kim KM, Huong LT, Yea SS, Cha IJ, Shin JG (2005) Genetic polymorphism of CYP2C9 in a Vietnamese Kinh population. Ther Drug Monit 27(2):208–210
Ota T, Kamada Y, Hayashida M, Iwao-Koizumi K, Murata S, Kinoshita K (2015) Combination analysis in genetic polymorphisms of drug-metabolizing enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in the Japanese population. Int J Med Sci 12(1):78–82
Bae JW, Choi CI, Kim MJ, Oh DH, Keum SK, Park JI, Kim BH, Bang HK, Oh SG, Kang BS, Park HJ, Kim HD, Ha JH, Shin HJ, Kim YH, Na HS, Chung MW, Jang CG, Lee SY (2011) Frequency of CYP2C9 alleles in Koreans and their effects on losartan pharmacokinetics. Acta Pharmacol Sin 32(10):1303–1308
Dai DP, Xu RA, Hu LM, Wang SH, Geng PW, Yang JF, Yang LP, Qian JC, Wang ZS, Zhu GH, Zhang XH, Ge RS, Hu GX, Cai JP (2014) CYP2C9 polymorphism analysis in Han Chinese populations: building the largest allele frequency database. Pharmacogenomics J 14(1):85–92
Ngow HA, Wan Khairina WM, Teh LK, Lee WL, Harun R, Ismail R, Salleh MZ (2009) CYP2C9 polymorphism: prevalence in healthy and warfarin-treated Malay and Chinese in Malaysia. Singapore Med J 50(5):490–493
Rusdiana T, Araki T, Nakamura T, Subarnas A, Yamamoto K (2013) Responsiveness to low-dose warfarin associated with genetic variants of VKORC1, CYP2C9, CYP2C19, and CYP4F2 in an Indonesian population. Eur J Clin Pharmacol 69(3):395–405
Nahar R, Deb R, Saxena R, Puri RD, Verma IC (2013) Variability in CYP2C9 allele frequency: a pilot study of its predicted impact on warfarin response among healthy South and North Indians. Pharmacol Rep 65(1):187–194
Zand N, Tajik N, Moghaddam AS, Milanian I (2007) Genetic polymorphisms of cytochrome P450 enzymes 2C9 and 2C19 in a healthy Iranian population. Clin Exp Pharmacol Physiol 34(1–2):102–105
Sükrü AA, Brockmöller J, Bauer S, Sachse C, Güzelbey P, Öngen Z, Nacak M, Roots I (1999) Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol 48(3):409–415
Pedersen RS, Brasch-Andersen C, Sim SC, Bergmann TK, Halling J, Petersen MS, Weihe P, Edvardsen H, Kristensen VN, Brøsen K, Ingelman-Sundberg M (2010) Linkage disequilibrium between the CYP2C19*17 allele and wildtype CYP2C8 and CYP2C9 alleles: identification of CYP2C haplotypes in healthy Nordic populations. Eur J Clin Pharmacol 66(12):1199–1205
Scordo MG, Caputi AP, D’Arrigo C, Fava G, Spina E (2004) Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population. Pharmacol Res 50(2):195–200
Scott SA, Khasawneh R, Peter I, Kornreich R, Desnick RJ (2010) Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups. Pharmacogenomics 11(6):781–791
Momeni D (1976) The population of Iran: a dynamic analysis. University of Texas at Austin, Austin
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This research is funded by Vietnam National Foundation for Science and Technology Development (NAFOSTED) under Grant Number 106-YS.02-2014.30.
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Vu, N.P., Ma, T.T.H., Tran, N.T.B. et al. Polymorphic analysis of CYP2C9 gene in Vietnamese population. Mol Biol Rep 45, 893–900 (2018). https://doi.org/10.1007/s11033-018-4235-3
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DOI: https://doi.org/10.1007/s11033-018-4235-3