Genetic polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in Vietnamese-Koreans

Ye-Ji Lim; Eun-Young Cha; Hye-Eun Jung; Jong-Lyul Ghim; Su-Jun Lee; Eun-Young Kim; Jae-Gook Shin

doi:10.12793/tcp.2014.22.2.70

Journal List > Transl Clin Pharmacol > v.22(2) > 1082597

Go to TopGo to Top Go to BottomGo to Bottom

TOOLS

Lim, Cha, Jung, Ghim, Lee, Kim, and Shin: Genetic polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in Vietnamese-Koreans

Original Article

Translational and Clinical Pharmacology 2014;22(2):70-77.

Published online: 30 December 2014

DOI: https://doi.org/10.12793/tcp.2014.22.2.70

Genetic polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in Vietnamese-Koreans

Ye-Ji Lim¹, Eun-Young Cha¹, Hye-Eun Jung¹, Jong-Lyul Ghim², Su-Jun Lee¹, Eun-Young Kim^2,^∗, Jae-Gook Shin^1,^2,^∗

¹Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614–735, Republic of Korea

²Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan 614–735, Republic of Korea

^∗Correspondence: J. G. Shin; Tel: +82-51-890-6709, Fax: +82-51-893-1232, E-mail: phshinjg@gmail.com; E. Y. Kim; Tel: +82-51-890-8972, Fax: +82-51-895-6438, E-mail: eykim@inje.ac.kr

Received 6 November 20142 December 2014 Accepted 3 December 2014

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The Vietnamese-Koreans, especially offspring between a Vietnamese mother and a Korean father constituted the highest proportion (64.2%) of total Kosian population according to a census in 2014. To evaluate genetic characteristics in the Vietnamese-Koreans, a total of 25 alleles from CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were genotyped using SNaPshot method with DNA samples of 127 Vietnamese-Koreans. The previous reports on the CYPs of Korean and Vietnamese populations were also analyzed for the comparative studies for the frequencies of CYP alleles. The statistical significances in allele and genotype frequencies among the ethnics were analyzed by Chi-square or Fisher's exact probability test. Although most of variants analyzed in 5 CYPs did not reach the statistically significant difference between the Vietnamese-Koreans and Vietnamese, some alleles were only found in Vietnamese-Koreans. Compared with Korean population, frequencies of CYP2D6∗1 and CYP2D6∗10B were statistically different from Vietnamese-Koreans (p<0.05). This is the first report to describe the CYP genotype profiles of Vietnamese-Koreans, which may provide important insight for the genotype based prediction of CYP activities of this admixture of Korean and Vietnamese.

Keywords: Racially mixed Korean, Cytochrome P450, Genetic polymorphism, Vietnamese, Korean

References

1. Kim GR, Choi GH. Dictionary of popular culture. Hyunsil Moonhwa Yeon Goo;2009.

2. Census of population of foreign residents in Korea. Korea Ministry of Public Administration and Security;2014.

3. Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics. 2002; 3:229–243.

4. Xie HG, Prasad HC, Kim RB, Stein CM. CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev. 2002; 54:1257–1270.

5. Ozawa S, Soyama A, Saeki M, Fukushima-Uesaka H, Itoda M, Koyano S, et al. Ethnic differences in genetic polymorphisms of CYP2D6, CYP2C19, CYP3As and MDR1/ABCB1. Drug Metab Pharmacokinet. 2004; 19:83–95.

6. Bernard S, Neville KA, Nguyen AT, Flockhart DA. Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications. Oncologist. 2006; 11:126–135.

7. Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet. 1997; 32:210–258.

8. Johansson I, Ingelman-Sundberg M. Genetic polymorphism and toxicology–with emphasis on cytochrome p 450. Toxicol Sci. 2011; 120:1–13. doi: 10.1093/toxsci/kfq374.

9. Wolf CR, Smith G. Pharmacogenetics. Br Med Bull. 1999; 55:366–386.

10. Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol. 1998; 45:525–538.

11. Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics. 2002; 12:251–263.

12. Lee SS, Kim KM, Thi-Le H, Yea SS, Cha IJ, Shin JG. Genetic polymorphism of CYP2C9 in a Vietnamese Kinh population. Ther Drug Monit. 2005; 27:208–210.

13. Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet. 2002; 41:913–958.

14. Goldstein JA, Ishizaki T, Chiba K, de Morais SM, Bell D, Krahn PM, et al. Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. Pharmacogenetics. 1997; 7:59–64.

15. Lee SJ, Kim WY, Kim H, Shon JH, Lee SS, Shin JG. Identification of new CYP2C19 variants exhibiting decreased enzyme activity in the metabolism of S-mephenytoin and omeprazole. Drug Metab Dispos. 2009; 37:2262–2269. doi: 10.1124/dmd.109.028175.

16. Kim KA, Song WK, Kim KR, Park JY. Assessment of CYP2C19 genetic polymorphisms in a Korean population using a simultaneous multiplex pyrosequencing method to simultaneously detect the CYP2C19∗2, CY-P2C19∗3, and CYP2C19∗17 alleles. J Clin Pharm Ther. 2010; 35:697–703. doi: 10.1111/j.1365-2710.2009.01069.x.

17. Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmacogenomics and individualized drug therapy. Annu Rev Med. 2006; 57:119–137.

18. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005. (5):6–13.

19. Bozina N, Bradamante V, Lovric M. Genetic polymorphism of metabolic enzymes P450 (CYP) as a susceptibility factor for drug response, toxicity, and cancer risk. Arh Hig Rada Toksikol. 2009; 60:217–242. doi: 10.2478/10004-1254-60-2009-1885.

20. Hu YF, He J, Chen GL, Wang D, Liu ZQ, Zhang C, et al. CYP3A5∗3 and CYP3A4∗18 single nucleotide polymorphisms in a Chinese population. Clin Chim Acta. 2005; 353:187–192.

21. Lee SJ, Lee SS, Jeong HE, Shon JH, Ryu JY, Sunwoo YE, et al. The CYP3A4∗18 allele, the most frequent coding variant in asian populations, does not significantly affect the midazolam disposition in heterozygous individuals. Drug Metab Dispos. 2007; 35:2095–2101.

22. Ruzilawati AB, Suhaimi AW, Gan SH. Genetic polymorphisms of CYP3A4: CYP3A4∗18 allele is found in five healthy Malaysian subjects. Clin Chim Acta. 2007; 383:158–162.

23. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001; 27:383–391.

24. Kim HS, Lee SS, Oh M, Jang YJ, Kim EY, Han IY, et al. Effect of CYP2C9 and VKORC1 genotypes on early-phase and steady-state warfarin dosing in Korean patients with mechanical heart valve replacement. Pharmacogenet Genomics. 2009; 19:103–112. doi: 10.1097/FPC.0b013e32831a9ae3.

25. Kim EY, Lee SS, Jung HJ, Jung HE, Yeo CW, Shon JH, et al. Robust CYP2D6 genotype assay including copy number variation using multiplex single-base extension for Asian populations. Clin Chim Acta. 2010; 411:2043–2048. doi: 10.1016/j.cca.2010.08.042.

26. Ku HY, Ahn HJ, Seo KA, Kim H, Oh M, Bae SK, et al. The contributions of cytochromes P450 3A4 and 3A5 to the metabolism of the phosphodiesterase type 5 inhibitors sildenafil, udenafil, and vardenafil. Drug Metab Dispos. 2008; 36:986–990. doi: 10.1124/dmd.107.020099.

27. Lee HW, Lim MS, Lee J, Jegal MY, Kim DW, Lee WK, et al. Frequency of CYP2C9 variant alleles, including CYP2C9∗13 in a Korean population and effect on glimepiride pharmacokinetics. J Clin Pharm Ther. 2012; 37:105–111. doi: 10.1111/j.1365-2710.2010.01238.x.

28. Lee SJ, Lee SS, Jung HJ, Kim HS, Park SJ, Yeo CW, et al. Discovery of novel functional variants and extensive evaluation of CYP2D6 genetic polymorphisms in Koreans. Drug Metab Dispos. 2009; 37:1464–1470. doi: 10.1124/dmd.108.022368.

29. Yoo HD, Cho HY, Lee YB. Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CY-P2C19 and ABCB1. Br J Clin Pharmacol. 2010; 69:27–37. doi: 10.1111/j.1365-2125.2009.03558.x.

30. Lee SS, Lee SJ, Gwak J, Jung HJ, Thi-Le H, Song IS, et al. Comparisons of CYP2C19 genetic polymorphisms between Korean and Vietnamese populations. Ther Drug Monit. 2007; 29:455–459.

31. Veiga MI, Asimus S, Ferreira PE, Martins JP, Cavaco I, Ribeiro V, et al. Pharmacogenomics of CYP2A6, CYP2B6, CYP2C19, CYP2D6, CY-P3A4, CYP3A5 and MDR1 in Vietnam. Eur J Clin Pharmacol. 2009; 65:355–363. doi: 10.1007/s00228-008-0573-8.

32. McGraw J, Waller D. Cytochrome P450 variations in different ethnic populations. Expert Opin Drug Metab Toxicol. 2012; 8:371–382. doi: 10.1517/17425255.2012.657626.

33. Jaja C, Burke W, Thummel K, Edwards K, Veenstra DL. Cytochrome p450 enzyme polymorphism frequency in indigenous and native american populations: a systematic review. Community Genet. 2008; 11:141–149. doi: 10.1159/000113876.

34. Bradford LD, Kirlin WG. Polymorphism of CYP2D6 in Black populations: implications for psychopharmacology. Int J Neuropsychopharmacol. 1998; 1:173–185.

35. Johansson I, Yue QY, Dahl ML, Heim M, Sawe J, Bertilsson L, et al. Genetic analysis of the interethnic difference between Chinese and Caucasians in the polymorphic metabolism of debrisoquine and codeine. Eur J Clin Pharmacol. 1991; 40:553–556.

36. Liu YT, Hao HP, Liu CX, Wang GJ, Xie HG. Drugs as CYP3A probes, inducers, and inhibitors. Drug Metab Rev. 2007; 39:699–721.

37. Xie HG, Wood AJ, Kim RB, Stein CM, Wilkinson GR. Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics. 2004; 5:243–272.

Table 1.

The allele frequencies of Vietnamese-Korean, Korean, and Vietnamese populations

Gene	Allele	Vietnamese-Korean^a)			Korean		Vietnamese
Gene	Allele	N^b)	(%)	95% CI^c)	N^d)	(%)	N^d)	(%)
CYP2C9	∗1	244	96.1	93.7 – 98.5	295 [27]	94.7	157 [12]	97.8
	∗3	8	3.2	1.0 – 5.3		5.1		2.2
	∗13	2	0.8	0.0 – 1.9		0.2		0
CYP2C19	∗1	170	66.9	61.1 – 72.7	271 [16]	60	165 [30]	68.8
	∗2	65	25.6	20.2 – 31		28.4		26.4
	∗3	14	5.5	2.7 – 8.3		10.1		4.9
	∗17	5	2	0.3 – 3.7		1.5		ND
CYP2D6	∗1	55	21.8	16.7 – 26.9	758 [28]	32.3	122 [25]	24.6
	∗2	20	7.9	4.6 – 11.3		10.1		7.8
	∗5	17	6.8	3.7 – 9.8		5.6		6.1
	∗10B	141	56	49.8 – 62.1		45.6		57.0
	∗14B	2	0.8	0.0 – 1.9		0.3		1.2
	∗18	0	0	0.0 – 0.0		0.3		0
	∗21B	1	0.4	0.0 – 1.2		0.3		0
	∗41	11	4.4	1.8 – 6.9		2.2		2.7
	∗49	3	1.2	0.0 – 2.5		1.4		0.4
	∗52	0	0	0.0 – 0.0		0.3		0
	∗60	0	0	0.0 – 0.0		0.1		0
	∗1XN	1	0.4	0.0 – 1.2		0.1		0
	∗2XN	0	0	0.0 – 0.0		1		0
	∗10BX2	1	0.4	0.0 – 1.2		0.4		0
CYP3A4	∗1	252	99.2	98.1 – 100.0	298 [21]	98.3	72 [31]	97.9
	∗1B	ND	ND			ND		2.1
	∗18	2	0.8	0.0 – 1.9		1.7		ND
CYP3A5	∗1	55	21.7	16.6 – 26.7	104 [29]	26	72 [31]	33.3
CYP3A5	∗3	199	78.4	73.3 – 83.4v		74		66.7

^a) 126 subjects for CYP2D6, 127 subjects for CYP2C9, CYP2C19, CYP3A4, and CYP3A5,

^b) Number of alleles,

^c) CI: confidence interval,

^d) Number of studied subjects

Table 2.

The frequencies of genotypes in Vietnamese-Korean, Korean, and Vietnamese populations

Genotype	Vietnamese-Korean^a)			Korean		Vietnamese
Genotype	No.t^b)	(%)	95% CI^c)	N^d)	(%)	N^d)	(%)
CYP2C9				295 [27]		157 [12]
∗1/∗1	117	92.1	87.4 – 96.8		88.7		95.5
∗1/∗3	8	6.3	2.1 – 10.5		10.6		7.0
∗1/∗13	2	1.6	0.0 – 3.7		0.4		0.0
CYP2C19				271 [16]		165 [30]
∗1/∗1	56	44.1	35.5 – 52.7		35.7		44.9
∗1/∗2	45	35.4	27.1 – 43.7		36.5		41.8
∗1/∗3	9	7.1	2.6 – 11.6		10.7		6.1
∗1/∗17	4	3.2	0.1 – 6.2		1.1		ND
∗2/∗2	7	5.5	1.5 – 9.5		5.9		4.2
∗2/∗3	5	3.9	0.6 – 7.3		7.0		2.4
∗2/∗17	1	0.8	0.0 – 2.3		1.4		ND
∗3/∗3	0	0.0	0.0 – 0.0		1.1		0.6
∗3/∗17	0	0.0			0.3		ND
CYP2D6				758 [28]
∗1/∗1	6	4.8	1 – 8.5		12.4		ND
∗1/∗2	8	6.4	2.1 – 10.6		5.9		ND
∗1/∗5	3	2.4	0.0 – 5.0		3.6		ND
∗1/∗10B	30	23.8	16.4 – 31.2		26.8		ND
∗1/∗14B	0	0.0	0.0 – 0.0		0.0		ND
∗1/∗21B	1	0.8	0.0 – 2.3		0.1		ND
∗1/∗41	0	0.0	0.0 – 0.0		1.1		ND
∗1/∗49	1	0.8	0.0 – 2.3		1.1		ND
∗1XN/∗1	0	0.0	0.0 – 0.0		0.3		ND
∗1XN/∗10B	1	0.8	0.0 – 2.3		0.0		ND
∗2/∗2	0	0.0	0.0 – 0.0		1.19		ND
∗2/∗5	2	1.6	0.0 – 3.8		1.2		ND
∗2/∗10B	7	5.6	1.6 – 9.6		9.9		ND
∗2/∗14	0	0.0	0.0 – 0.0		0.1		ND
∗2/∗18	0	0.0	0.0 – 0.0		0.1		ND
∗2/∗21	0	0.0	0.0 – 0.0		0.1		ND
∗2/∗41	3	2.4	0.0 – 5.0		0.1		ND
∗2/∗52	0	0.0	0.0 – 0.0		0.3		ND
∗2XN/∗1	0	0.0	0.0 – 0.0		0.92		ND
∗2XN/∗5	0	0.0	0.0 – 0.0		0.1		ND
∗2XN/∗10B	0	0.0	0.0 – 0.0		0.9		ND
∗5/∗5	0	0.0	0.0 – 0.0		0.3		ND
∗5/∗10B	9	7.1	2.6 – 11.6		5.5		ND
∗5/∗10BX2	1	0.8	0.0 – 2.3		0.0		ND
∗5/∗14	0	0.0	0.0 – 0.0		0.1		ND
∗5/∗41	1	0.8	0.0 – 2.3		0.13		ND
∗5/∗49	1	0.8	0.0 – 2.3		0.0		ND
∗10B/∗10B	42	33.3	25.1 – 41.6		20.8		ND
∗10B/∗14B	2	1.6	0.0 – 3.8		0.3		ND
∗10B/∗18	0	0.0	0.0 – 0.0		0.4		ND
∗10B/∗21	0	0.0	0.0 – 0.0		0.4		ND
∗10B/∗41	7	5.6	1.6 – 9.6		2.5		ND
∗10B/∗49	1	0.8	0.0 – 2.3		1.6		ND
∗10B/∗52	0	0.0	0.0 – 0.0		0.3		ND
∗10B/∗60	0	0.0	0.0 – 0.0		0.1		ND
∗10/∗10XN	0	0.0	0.0 – 0.0		0.8		ND
∗14/∗41	0	0.0	0.0 – 0.0		0.1		ND
∗41/∗41	0	0.0	0.0 – 0.0		0.3		ND
∗49/∗52	0	0.0	0.0 – 0.0		0.1		ND
CYP3A4
∗1/∗1	125	98.4	96.3 – 100.0		ND		ND
∗1A/∗1A	ND	ND			ND		95.9
∗1A/∗1B	ND	ND			ND		4.1
∗1/∗18	2	1.6	0.0 – 3.7		ND		ND
CYP3A5				104 [29]		74 [31]
∗1/∗1	5	3.9	0.6 – 7.3		5.8		9.5
∗1/∗3	45	35.4	27.1 – 43.7		40.4		44.6
∗3/∗3	77	60.6	52.1 – 69.1		53.8		45.9

^a) 126 subjects for CYP2D6, 127 subjects for CYP2C9, CYP2C19, CYP3A4, and CYP3A5,

^b) Number of detected subjects,

^c) CI: confidence interval,

^d) Number of studied subjects

TOOLS

Similar articles