Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Association Study between Genetic Polymorphisms of CYP2C19 Gene and Essential Hypertension in Koreans

한국인에서 CYP2C19 유전자 다형성과 본태성 고혈압 간의 연관성 연구

  • Park, Ah-Ram (Cardiovascular Genome Center, Yonsei University College of Medicine) ;
  • Shin, Eun-Soon (DNA Link Inc.) ;
  • Son, Nak-Hoon (Cardiovascular Genome Center, Yonsei University College of Medicine) ;
  • Jang, Yang-Soo (Cardiovascular Genome Center, Yonsei University College of Medicine) ;
  • Shin, Dong-Jik (Cardiovascular Genome Center, Yonsei University College of Medicine)
  • 박아람 (심혈관계질환 유전체연구센터) ;
  • 신은순 (DNA Link (주)) ;
  • 손낙훈 (심혈관계질환 유전체연구센터) ;
  • 장양수 (심혈관계질환 유전체연구센터) ;
  • 신동직 (심혈관계질환 유전체연구센터)
  • Received : 2010.04.01
  • Accepted : 2010.04.28
  • Published : 2010.05.31
Download PDF
⟨ Previous Next ⟩

Abstract

In humans, CYP2C19, a member of the cytochrome P450 subfamily, metabolizes arachidonic acid to produce epoxyicosanoid acids, which are involved in vascular tone and regulation of blood pressure (BP). Recent findings suggest that CYP2C19 gene polymorphisms might be considered as a novel candidate gene for cardiovascular disease. We thus focused on the Korean population to explore the association of two polymorphisms ($CYP2C19^*2$ and $^*3$) in this gene and essential hypertension (EH). A total of 1,241 participants (537 hypertensive subjects and 704 healthy controls) were recruited from the Yonsei Cardiovascular Genome Center in Korea. The CYP2C19 polymorphisms were genotyped using the $SNaPShot^{TM}$ assay. The allele and genotype frequencies of $CYP2C19^*3$ showed significant difference between hypertensives and normotensives (P=0.019 and P=0.023, respectively). Logistic regression analysis indicated that the $CYP2C19^*3$ A allele carriers were significantly associated with EH (OR, 0.723; 95% CI, 0.538-0.972, P=0.032) under a dominant model. In addition, CYP2C19 G-A haplotype ($2C19^*2\;G-^*3$ A combination) was found to significantly reduce EH risk (OR, 0.714, P=0.015). We believe this provides evidence that $CYP2C19^*3$ polymorphism may contribute to a protective effect in the development of EH.

혈관 수축력 및 혈압 조절에 관여하는 것으로 알려진 아라키돈산을 물질 대사시키는 CYP2C19 유전자는 최근 심혈관 질환 관련 연구의 새로운 유전자로 제시되고 있다. 본 연구에서는 CYP2C19 유전자의 2 종류 다형성 ($CYP2C19^*2$와 $CYP2C19^*3$)과 고혈압 간의 연관성을 조사하고자 하였다. 연세대학교 의료원 심장혈관병원에서 수집한 1,241명(환자군: 537명, 대조군: 704명)을 대상으로 $SNaPShot^{TM}$ assay를 이용하여 유전자형을 결정하였다. 두 종류의 다형성 가운데 $CYP2C19^*3$의 대립인자형 및 유전자형의 빈도 분포가 환자군과 대조군 간에 유의한 차이를 나타냈다(p=0.019, p=0.023). 다중 로지스틱 회귀분석 결과, dominant model에서, CYP2C193 A 대립인자형은 본태성 고혈압과 매우 유의한 연관성을 나타냈다(OR, 0.723, p=0.032). 또한 CYP2C19 G-A haplotype은 고혈압 발생 위험을 매우 유의하게 감소시키는 것으로 조사되었다(OR, 0.714, p=0.015). 따라서 본 연구 결과는 $CYP2C19^*3$ 다형성이 본태성 고혈압 발생에 대한 보호 효과작용에 관여할 것이라는 증거를 제시하고자 한다.

Keywords

References

  1. Aynacioglu, A. S., C. Sachse, A. Bozkurt, S. Kortunay, M. Nacak, T. Schroder, S. O. Kayaalp, I. Roots, and J. Brockmoller. 1999. Low frequency of defective alleles of cytochrome P450 enzymes 2C19 and 2D6 in the Turkish population. Clin. Pharmacol. Ther. 48, 409-415.
  2. Bae, Y., C. Park, J. Han, Y. J. Hong, H. H. Song, E. S. Shin, J. E. Lee, B. G. Han, Y. Jang, D. J. Shin, and S. K. Yoon. 2007. Interaction between GNB3 C825T and ACE I/D polymorphisms in essential hypertension in Koreans. J. Hum. Hypertens. 21, 159-166. https://doi.org/10.1038/sj.jhh.1002110
  3. Bertrand-Thiebault, C., H. Berrahmoune, A. Thompson, B. Marie, S. Droesch, G. Siest, D. Foernzler, and S. Visvikis-Siest. 2008. Genetic polymorphisms of CYP2C19 gene in the Stanislas Cohort. A link with inflammation. Ann. Hum. Genet. 72, 178-183. https://doi.org/10.1111/j.1469-1809.2007.00417.x
  4. Chen, L., S. Qin, J. Xie, J. Tang, L. Yang, W. Shen, X. Zhao, J. Du, G. He, G. Feng, L. He, and Q. Xing. 2008. Genetic polymorphisms analysis of CYP2C19 in Chinese Han populations from different geographic areas of mainland China. Pharmacogenomics 9, 691-702. https://doi.org/10.2217/14622416.9.6.691
  5. De Morais, S. M., G. R. Wilkinson, J. Blaisdell, U. A. Meyer, K. Nakamura, and J. A. Goldstein. 1994. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol. Pharmacol.46, 594-598.
  6. De Morais, S. M., G. R. Wilkinson, J. Blaisdell, K. Nakamura, U. A. Meyer, and J. A. Goldstein. 1994. The major genetic defect responsible for the polymorphism S-mephenytoin metabolism in humans. J. Biol. Chem. 269, 15419-15422.
  7. Friedewald, W. T., R. I. Levy, and D. S. Fredrickson. 1972. Estimation of concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin. Chem. 18, 499-502.
  8. Fukushima-Uesaka, H., Y. Saito, K. Maekawa, S. Ozawa, R. Hasegawa, H. Kajio, N. Kuzuya, K. Yasuda, M. Kawamoto, N. Kamatani, K. Suzuki, T. Yanagawa, M. Tohkin, and J. I. Sawada. 2005. Genetic variations and haplotypes of CYP2C19 in a Japanese population. Drug Metab. Pharmacokinet. 20, 300-307. https://doi.org/10.2133/dmpk.20.300
  9. Goldstein, J. A. 2001. Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br. J. Clin. Pharmacol. 52, 349-355. https://doi.org/10.1046/j.0306-5251.2001.01499.x
  10. Goldstein, J. A., T. Ishizaki, K. Chiba, S. M. de Morais, D. Bell, P. M. Krahn, and D. A. Evans. 1997. Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental,Caucasian, Saudi Arabian and American black populations. Pharmacogenetics 7, 59-64. https://doi.org/10.1097/00008571-199702000-00008
  11. Gray, I. C., C. Nobile, R. Muresu, S. Ford, and N. K. Spurr. 1995. A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24. Genomics 28, 328-332. https://doi.org/10.1006/geno.1995.1149
  12. Harrap, S. B. 1994. Hypertension: genes versus environment. Lancet 344, 169-171. https://doi.org/10.1016/S0140-6736(94)92762-6
  13. Herrlin, K., A. Y. Massele, M. Jande, C. Alm, G. Tybring, Y. A. Abdi, A. Wennerholm, I. Johansson, M. L. Dahl, L. Bertilsson, and L. L. Gustafsson. 1998. Bantu Tanzanians have a decreased capacity to metablolize omeprazole and mephenytoin in relation to their CYP2C19 genotype. Clin. Pharmacol. Ther. 64, 391-401. https://doi.org/10.1016/S0009-9236(98)90070-4
  14. Lee, S. S., S. J. Lee, J. Gwak, H. J. Jung, H. Thi-Le, I. S. Song, E. Y. Kim, and J. G. Shin. 2007. Comparisons of CYP2C19 genetic polymorphisms between Korean and Vietnamese populations. Ther. Drug Monit. 29, 455-459. https://doi.org/10.1097/FTD.0b013e31811f383c
  15. Lee, J. M., S. H. Park, D. J. Shin, D. H. Choi, C. Y. Shim, Y. G. Ko, J. S. Kim, E. S. Shin, C. W. Chang, J. E. Lee, and Y. S. Jang. 2009. Relation of genetic polymorphisms in the cytochrome P450 gene with Clopidogrel resistance afterdrug-eluting stent implantation in Koreans. Am. J. Cardiol. 104, 46-51. https://doi.org/10.1016/j.amjcard.2009.02.045
  16. Ozawa, S., A. Soyama, M. Saeki, H. Fukushima-Uesaka, M. Itoda, S. Koyano, Y. Ohno, Y. Saito, and J. Sawada. 2004. Ethnic differences in genetic polymorphisms of CYP2D6, CYP2C19, CYP3As and MDR1/ABCB1. Drug Metab. Pharmacokinet. 17, 150-156.
  17. Rahman, M., J. T. Wright, and J. G. Douglas. 1997. The role of cytochrome P450 dependent metabolites of arachidonic acid in blood pressure regulation and renal function. Am. J. Hypertens. 10, 356-365. https://doi.org/10.1016/S0895-7061(96)00381-0
  18. Roh, H. K., M. L. Dahl, G. Tybring, H. Yamada, Y. N. Cha, and L. Bertilsson. 1996. Debrisoquine and S- mephenytoin hydroxylation phenotypes and genotypes in a Korean population. Pharmacogenetics 6, 441-447. https://doi.org/10.1097/00008571-199610000-00008
  19. Scordo, M. G., A. P. Caputi, C. D’Arrigo, G. Fava, and E. Spina. 2004. Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population. Pharmacol. Res. 50, 195-200. https://doi.org/10.1016/j.phrs.2004.01.004
  20. Taguchi, M., T. Nozawa, K. Mizumaki, H. Inoue, K. Tahara, C. Takesono, and Y. Hashimoto. 2004. Nonlinear mixed effects model analysis of the pharmacokinitics of metoprolol in routinely treated Japanese patients. Biol. Pharm. Bull. 27, 1642-1648. https://doi.org/10.1248/bpb.27.1642
  21. Tassaneeyakul, W., W. Mahatthanatrakul, K. Niwatananun, K. Na-Bangchang, A. Tawalee, N. Krikreangsak, U. Cykleng, and W. Tassaneeyakul. 2006. CYP2C19 genetic polymorphism in Thai, Burmese and Karen populations. Drug Metab. Pharmacokinet. 21, 286-290. https://doi.org/10.2133/dmpk.21.286
  22. Turner, S. T., E. Boerwinkle, and C. F. Sing. 1999. Context-dependent associations of the ACE I/D polymorphism with blood pressure. Hypertension 34, 773-778. https://doi.org/10.1161/01.HYP.34.4.773
  23. Xie, H. G., C. M. Stein, R. B. Kim, G. R. Wilkinson, D. A. Flockhart, and A. J. Wood. 1999. Allelic, genotypic distributions of S-mephenytoin 4’-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics 9, 539-549. https://doi.org/10.1097/00008571-199910000-00001
  24. Yamada, S., M. Onda, S. Kato, N. Matsuda, T. Matsuhisa, N. Yamada, M. Miki, and N. Matsukura. 2001. Genetic differences in CYP2C19 single nucleotide polymorphisms among four Asian populations. J. Gastroenterol. 36, 696-699. https://doi.org/10.1007/s005350170033
  25. Zand, N., N. Tajik, A. S. Moghaddam, and I. Milanian. Genetic polymorphisms of cytochrome P450 enzymes 2C9 and 2C19 in a healthy Iranian population. Clin. Exp. Pharmacol. Physiol. 34, 2-5.