Association of the COMT Gene Polymorphism with the Risk of PCOS in Korean Women

한국인 여성에서 다낭성난소증후군의 발생 위험도와 Catechol-O-Methyltransferase 유전자 다형성과의 관련성에 관한 연구

  • Lee, Ji Young (Department of Obstetrics and Gynecology, College of Medicine, Konkuk University) ;
  • Cha, Yun Jeong (Department of Obstetrics and Gynecology, College of Medicine, Konkuk University) ;
  • Hur, Seung Eun (Department of Obstetrics and Gynecology, College of Medicine, Konyang University) ;
  • Kwon, Han Sung (Department of Obstetrics and Gynecology, College of Medicine, Konkuk University) ;
  • Lee, Sun-Joo (Department of Obstetrics and Gynecology, College of Medicine, Konkuk University) ;
  • Sohn, In Sook (Department of Obstetrics and Gynecology, College of Medicine, Konkuk University) ;
  • Kim, Soo Nyung (Department of Obstetrics and Gynecology, College of Medicine, Konkuk University) ;
  • Seung, Yon A (Department of Internal Medicine, College of Medicine, Ewha Womans University) ;
  • Chung, Hye Won (Department of Obstetrics and Gynecology, College of Medicine, Ewha Womans University)
  • 이지영 (건국대학교 의과대학 산부인과학교실) ;
  • 차윤정 (건국대학교 의과대학 산부인과학교실) ;
  • 허성은 (건양대학교 의과대학 산부인과학교실) ;
  • 권한성 (건국대학교 의과대학 산부인과학교실) ;
  • 이선주 (건국대학교 의과대학 산부인과학교실) ;
  • 손인숙 (건국대학교 의과대학 산부인과학교실) ;
  • 김수녕 (건국대학교 의과대학 산부인과학교실) ;
  • 성연아 (이화여자대학교 의과대학 내과학교실) ;
  • 정혜원 (이화여자대학교 의과대학 산부인과학교실)
  • Published : 2006.06.30

Abstract

Objective: To investigate whether polymorphism of Catechol-O-methyltransferase(COMT) gene is associated with the risk of polycystic ovary syndrome (PCOS) in Korean women. Methods: One hundred and thirty-six PCOS patients and eighty four controls were enrolled. Blood samples were collected from the patients diagnosed according to the 2003 revised criteria of the Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Age matched women with regular menstruation from same geographic region were recruited as control subject. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) of PCR products were done to determine all individuals' genotype. Results: In women with $COMT^{LL}$ genotype, there was decreased PCOS risk and this difference was statistically significant (OR 0.24, 95% CI 0.11~0.51). Conclusion: The results suggest that the $COMT^{LL}$ genetic polymorphism might be associated with PCOS risk in Korean women.

연구목적 : 한국인 여성에서 에스트로겐의 대사 및 불활성화와 관련된 COMT 유전자 다형성과 다낭성 난소증후군의 발생 위험도의 관련성을 알아보고자 하였다. 연구방법 : 연구대상자는 2003년 ESHRE의 진단기준을 만족하는 다낭성 난소증후군 여성 136명과 연령이 비슷하며 규칙적인 생리를 하는 여성 84명의 대조군을 대상으로 하였다. 연구대상자들의 genomic DNA는 혈액에서 추출하였으며, PCR 및 RFLP를 이용하여 유전자 다형성을 조사하였다. 결과 : COMT를 코딩하는 유전자의 exon4에서 $G{\rightarrow}A$로의 다형성을 조사한 결과 오히려 저활성 유전자형인 $COMT^{LL}$ 군에서 통계적으로 유의하게 다낭성 난소증후군의 발생 위험도가 낮아지는 것으로 나타났다(OR 0.241(CI 0.114~0.508)). 결론 : 이상의 결과로 볼 때 저활성 유전자형인 $COMT^{LL}$ 다형성 군에서 한국인 다낭성 난소증후군 발생이 감소하였으며, 에스트로겐 의존형 질환이 증가함에도 혈중 에스트라디올의 농도가 높지 않은 것은 다낭성 난소증후군 환자에서 $COMT^{HH}$ 다형성군이 증가되어 있는 것과 관련된 것으로 사료된다.

Keywords

Acknowledgement

Supported by : 건국대학교

References

  1. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935; 29: 181-91 https://doi.org/10.1016/S0002-9378(15)30642-6
  2. Nestler JE. Polycystic ovary syndrome: a disorder for the generalist. Fertil Steri 1998; 70: 811-2 https://doi.org/10.1016/S0015-0282(98)00318-5
  3. Clayton RN, Ogden V, Hodgkinson J, Worswick L, Rodin DA, Dyer S, et al. How common are polycystic ovaries in normal women and what is their significance for fertility of the population- Clin Endocrinol 1992; 37: 127-34 https://doi.org/10.1111/j.1365-2265.1992.tb02296.x
  4. Ferrima D, Puridie AW. The inheritance of polycystic ovarian disease and a possible relationship to premature balding. Clin Endocrinol 1979; 11: 291 -30 https://doi.org/10.1111/j.1365-2265.1979.tb03077.x
  5. Jahanfar S, Eden JA, Warren P, Seppala M, Nguyen TV. A twin study of polycystic ovarian syndrome. Fertil Steril 1995; 63: 478-86 https://doi.org/10.1016/S0015-0282(16)57412-3
  6. Abbott DH, Dumesic DA, Franks S. Developmental origin of polycystic ovary syndrome - a hypothesis. J Endocrinol 2002; 174: 1-5 https://doi.org/10.1677/joe.0.1740001
  7. Legro RS, Kunselman AR, Demers L, Wang SC, Bentley-Lewis R, Dunaif A. Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2002; 87: 2134 -8 https://doi.org/10.1210/jc.87.5.2134
  8. Gharani N, Waterworth DM, Batty S, White D, Gilling-Smith C, Conway GS, et al. Association of the steroid synthesis gene $CYP11\alpha$ with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet 1997; 6: 397-402
  9. Franks S. Polycystic ovary syndrome. N Engl J Med 1995; 333: 853-61 https://doi.org/10.1056/NEJM199509283331307
  10. Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 1995; 96: 801-10 https://doi.org/10.1172/JCI118126
  11. Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol 1992; 36: 105-11 https://doi.org/10.1111/j.1365-2265.1992.tb02909.x
  12. Venturoli S, Porcu E, Fabbri R, Magrini O, Gammi L, Paradisi R, et al. Episodic pulsatile secretion of FSH, LH, prolactin, oestradiol, oestrone, and LH, circadian variations in polycystic ovary syndrome. Clin Endocrinol 1988; 28: 93-107 https://doi.org/10.1111/j.1365-2265.1988.tb01208.x
  13. Wajchenberg BL, Achando SS, Mathor MM, Czeresnia CE, Giannella ND. Kirschner MA. The source(s) of estrogen production in hirsute women with polycystic ovarian disease as determined by simultaneous adrenal and ovarian venous catheterization. Fertil Steril 1988; 49: 56-61 https://doi.org/10.1016/S0015-0282(16)59648-4
  14. Yager JD, Liehr JG. Molecular mechanisms of estrogen carcinogenesis. Annu Rev Pharmacol Toxicol 1996; 36: 203-32 https://doi.org/10.1146/annurev.pa.36.040196.001223
  15. Zhu BT, Conney AH. Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis 1998; 19: 1-27 https://doi.org/10.1093/carcin/19.1.1
  16. Worda C, Sator MO, Schneeberger C, Jantschev T, Ferlitsch K, Huber JC. Influence of the catechol-Omethyltransferase (COMT) codon 158 polymorphism on estrogen levels in women. Hum Reprod 2003; 18: 262-6 https://doi.org/10.1093/humrep/deg059
  17. Millikan RC, Pittman GS, Tse CKJ, Duell E, Newman B, Savitz D, et al. Catechol-O-methyltransferase and breast cancer risk. Carcinogenesis 1998; 19: 1943-7 https://doi.org/10.1093/carcin/19.11.1943
  18. Thompson PA, Shields PG, Freudenheim JL, Stone A, Vena JE, Marshall JR, et al. Genetic polymorphisms in catechol-O-methyltransferase, menopausal status, and breast cancer risk. Cancer Res 1998; 58: 2107-10
  19. Yim DS, Parkb SK, Yoo KY, Yoon KS, Chung HH, Kang HL, et al.Relationship between the Va1158Met polymorphism of catechol O-methyl transferase and breast cancer. Pharmacogenetics 2001; 11: 279-86 https://doi.org/10.1097/00008571-200106000-00001
  20. 이사라, 이소현, 이운정, 허성은, 이지영, 문혜성 등. 한국 영성에서 자궁내막증의 발생 위험 도와 Catechol-O-Methyltransferase 유전자 다형성과의 관련성에 관한 연구. 대한불임회지 2004;31:51-7
  21. Park TW, Yoon KS, Kim JH, Park WY, Hirvonene A, Kang D. Functional catechol-O-methyltransferase gene polymorphism and susceptibility to schizophrenia. Eur Neuropsychopharmacol 2002; 12: 299-303
  22. Wu AH, Tseng CC, Van Den Berg D, Yu Me. Tea intake, COMT genotype, and breast cancer in AsianAmerican women. Cancer Res 2003; 63: 7526-9
  23. Chang RJ, Mandel FP, Lu JKH, Judd HL. Enhanced disparity of gonadotropin seretion by estrone in women with polycystic ovary disease. J Clin Endocrinol Metab 1982; 54: 490-4 https://doi.org/10.1210/jcem-54-3-490
  24. Barbieri RL, Markris A, Randall RW, Daniels G, Kistner RW, Ryan KJ. Insulin stimulates androgen accumulation in incubation of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 1986; 62: 904-10 https://doi.org/10.1210/jcem-62-5-904
  25. Tenhunen J, Heikkila P, Alanko A, Heinonen E, Akkila J, Ulmanen J. Soluble and membrane-bound catechol-O-methyltransferase in normal and malignant manunary gland. Cnacer Lett 1999; 144: 75 -84 https://doi.org/10.1016/S0304-3835(99)00197-4
  26. Huber JC, Schneeberger C, Tempfer CB. Genetic modelling of the estrogen metabolism as a risk factor of hormone-dependent disorders. Maturitas 2002; 42: 1-12 https://doi.org/10.1016/S0378-5122(02)00021-X
  27. Lavigne JA, Helzlsouer KJ, Huang HY, Strickland PT, Bell DA, Selmin O, et al. An association between the allele coding for a low activity variant of catechol-O-methyltransferase and the risk for breast cancer. Cancer Res 1997; 57: 5493-7
  28. Lavigne JA, Helzlsouer J, Huang HY, Strickland PT, Bell DA. An association between allele coding for a low activity variant of catechol O-methyltransferase and the risk for breast cancer. Cancer Res 1997; 57: 5493-7
  29. Palmatier MA, Kang AM, Kidd KK. Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol Psychiatry 1999; 46: 557-67 https://doi.org/10.1016/S0006-3223(99)00098-0
  30. Huang CS, Chem HD, Chang KJ, Cheng CW, HSU SM, Shen Cy' Breast cancer risk associated with genotype polymorphism of the estrogen-metabolizing genes CYF 17, CYF 1A, and COMT: a multigene study on cancer susceptibility. Cancer Res 1999; 59: 4870-5
  31. Goodman JE, Lavigne JA, Hengstler JG, Tanner B, He1zlsouer KJ, Yager JD. Catechol-O-methyltransferase polymorphism is not associated with ovarian cancer risk. Pharmacogenetics 2001; 11: 279-86 https://doi.org/10.1097/00008571-200106000-00001
  32. Zimarina TC, Kristensen VN, Imianitov EN, Bershtein LM. Polymorphisms of CYP1B1 and COMT in breast and endometrial cancer. Mol Biol (Mosk) 2004; 38: 386-93
  33. McGrath M, Hankinson SE, Arbeitrnan L, Colditz GA, Hunter DJ, De Vivo I. Cytochrome P450 1B1 and catechol-O-methyltransferase polyrnorphisms and endometrial cancer susceptibility. Carcinogenesis 2004; 25: 559-65 https://doi.org/10.1093/carcin/bgh039