Journal of Assisted Reproduction and Genetics

, Volume 34, Issue 1, pp 139–147 | Cite as

Single nucleotide polymorphisms in the TGF-β1 gene are associated with polycystic ovary syndrome susceptibility and characteristics: a study in Korean women

  • Eun Youn Roh
  • Jong Hyun Yoon
  • Eun Young Song
  • Jin Ju Kim
  • Kyu Ri Hwang
  • Soo Hyun Seo
  • Sue ShinEmail author



Although many hypotheses regarding the pathogenesis of polycystic ovary syndrome (PCOS) have been generated, genetic studies have not identified specific genes that play a role in PCOS etiopathogenesis. This study aimed to investigate the relationship between TGF-β1 gene polymorphism and PCOS in Koreans.


A total of 51 Korean women with PCOS and 69 healthy women were enrolled. We analyzed 4 single nucleotide polymorphisms (SNPs) of the TGF-β1 gene (rs11466313, rs1800469, rs2317130, and rs4803457). We also analyzed laboratory measurements, such as free testosterone, glucose, and cholesterol.


The frequencies of rs1800469T allele negativity, rs4803457T allele negativity, the rs1800469CC genotype, and the rs4803457CC genotype showed positive associations with PCOS (P = 0.003, P = 0.027, P = 0.009, and P=0.031, respectively), whereas the haplotypes rs1800469C–rs4803457T and rs1800469T–rs4803457T showed negative associations with PCOS. A strong protective effect of the “rs1800469CT–rs4803457TT” combination (OR = 0.09) and a strong risk effect of “rs1800469CC–rs4803457CC” (OR = 6.23) for PCOS were observed. The rs1800469C/T and rs2317130C/T SNPs exhibited associations with several laboratory measurements with various levels of significance.


The results demonstrated an association of TGF-β1 gene polymorphisms with the development and/or characteristics of PCOS in the Korean population.


Polycystic ovary syndrome TGF-β1 gene polymorphism Testosterone Korean 


Compliance with ethical standards

This study complied with ethical standards. Study design, including subject enrollment and informed consent, were approved by the Institutional Review Board of Seoul National University Boramae Medical Center (16-2015-144).

Conflict of interest

The authors declare that they have no conflict of interest.


No funding to report for this submission.


  1. 1.
    Dumitrescu R, Mehedintu C, Briceag I, Purcarea VL, Hudita D. The polycystic ovary syndrome: an update on metabolic and hormonal mechanisms. J Med Life. 2015;8:142–5.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Lujan ME, Chizen DR, Pierson RA. Diagnostic criteria for polycystic ovary syndrome: pitfalls and controversies. J Obstet Gynaecol Can. 2008;30:671–9.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Thathapudi S, Kodati V, Erukkambattu J, Katragadda A, Addepally U, Hasan Q. Tumor necrosis factor-alpha and polycystic ovarian syndrome: a clinical, biochemical, and molecular genetic study. Genet Test Mol Biomarkers. 2014;18:605–9. doi: 10.1089/gtmb.2014.0151.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Diao X, Han T, Zhang Y, Ma J, Shi Y, Chen ZJ. Family association study between tumour necrosis factor a gene polymorphisms and polycystic ovary syndrome in Han Chinese. Reprod Biomed Online. 2014;29:581–7. doi: 10.1016/j.rbmo.2014.07.005.CrossRefPubMedGoogle Scholar
  5. 5.
    Yang J, Zhong T, Xiao G, Chen Y, Liu J, Xia C, et al. Polymorphisms and haplotypes of the TGF-beta1 gene are associated with risk of polycystic ovary syndrome in Chinese Han women. Eur J Obstet Gynecol Reprod Biol. 2015;186:1–7. doi: 10.1016/j.ejogrb.2014.11.004.CrossRefPubMedGoogle Scholar
  6. 6.
    Hatzirodos N, Bayne RA, Irving-Rodgers HF, Hummitzsch K, Sabatier L, Lee S, et al. Linkage of regulators of TGF-beta activity in the fetal ovary to polycystic ovary syndrome. FASEB J. 2011;25:2256–65. doi: 10.1096/fj.11-181099.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Soter MO, Ferreira CN, Sales MF, Candido AL, Reis FM, Milagres KS, et al. Peripheral blood-derived cytokine gene polymorphisms and metabolic profile in women with polycystic ovary syndrome. Cytokine. 2015;76:227–35. doi: 10.1016/j.cyto.2015.06.008.CrossRefPubMedGoogle Scholar
  8. 8.
    Tumu VR, Govatati S, Guruvaiah P, Deenadayal M, Shivaji S, Bhanoori M. An interleukin-6 gene promoter polymorphism is associated with polycystic ovary syndrome in South Indian women. J Assist Reprod Genet. 2013;30:1541–6. doi: 10.1007/s10815-013-0111-1.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Raja-Khan N, Kunselman AR, Demers LM, Ewens KG, Spielman RS, Legro RS. A variant in the fibrillin-3 gene is associated with TGF-beta and inhibin B levels in women with polycystic ovary syndrome. Fertil Steril. 2010;94:2916–9. doi: 10.1016/j.fertnstert.2010.05.047.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Tal R, Seifer DB, Shohat-Tal A, Grazi RV, Malter HE. Transforming growth factor-beta1 and its receptor soluble endoglin are altered in polycystic ovary syndrome during controlled ovarian stimulation. Fertil Steril. 2013;100:538–43. doi: 10.1016/j.fertnstert.2013.04.022.CrossRefPubMedGoogle Scholar
  11. 11.
    Raja-Khan N, Urbanek M, Rodgers RJ, Legro RS. The role of TGF-beta in polycystic ovary syndrome. Reprod Sci. 2014;21:20–31. doi: 10.1177/1933719113485294.CrossRefPubMedGoogle Scholar
  12. 12.
    Rotello RJ, Lieberman RC, Purchio AF, Gerschenson LE. Coordinated regulation of apoptosis and cell proliferation by transforming growth factor beta 1 in cultured uterine epithelial cells. Proc Natl Acad Sci U S A. 1991;88:3412–5.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Urbanek M, Sam S, Legro RS, Dunaif A. Identification of a polycystic ovary syndrome susceptibility variant in fibrillin-3 and association with a metabolic phenotype. J Clin Endocrinol Metab. 2007;92:4191–8. doi: 10.1210/jc.2007-0761.CrossRefPubMedGoogle Scholar
  14. 14.
    Ewens KG, Stewart DR, Ankener W, Urbanek M, McAllister JM, Chen C, et al. Family-based analysis of candidate genes for polycystic ovary syndrome. J Clin Endocrinol Metab. 2010;95:2306–15. doi: 10.1210/jc.2009-2703.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Stener-Victorin E, Holm G, Labrie F, Nilsson L, Janson PO, Ohlsson C. Are there any sensitive and specific sex steroid markers for polycystic ovary syndrome? J Clin Endocrinol Metab. 2010;95:810–9. doi: 10.1210/jc.2009-1908.CrossRefPubMedGoogle Scholar
  16. 16.
    Chang WY, Knochenhauer ES, Bartolucci AA, Azziz R. Phenotypic spectrum of polycystic ovary syndrome: clinical and biochemical characterization of the three major clinical subgroups. Fertil Steril. 2005;83:1717–23.CrossRefPubMedGoogle Scholar
  17. 17.
    Kim JJ, Choi YM, Cho YM, Hong MA, Chae SJ, Hwang KR, Hwang SS, Yoon SH, Moon SY. Polycystic ovary syndrome is not associated with polymorphisms of the TCF7L2, CDKAL1, HHEX, KCNJ11, FTO and SLC30A8 genes. Clin Endocrinol (Oxf). 2012;77:439–45; doi: 10.1111/j.1365-2265.2012.04389.x.
  18. 18.
    Li L, Ryoo JE, Lee KJ, Choi BC, Baek KH. Genetic variation in the Mcp-1 gene promoter associated with the risk of polycystic ovary syndrome. PLoS One. 2015;10:e0123045. doi: 10.1371/journal.pone.0123045.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kim JW, Lee MH, Park JE, Yoon TK, Lee WS, Shim SH. Association of IL-18 genotype with impaired glucose regulation in Korean women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2012;161:51–5. doi: 10.1016/j.ejogrb.2011.12.008.CrossRefPubMedGoogle Scholar
  20. 20.
    Kim JJ, Choung SH, Choi YM, Yoon SH, Kim SH, Moon SY. Androgen receptor gene CAG repeat polymorphism in women with polycystic ovary syndrome. Fertil Steril. 2008;90:2318–23. doi: 10.1016/j.fertnstert.2007.10.030.CrossRefPubMedGoogle Scholar
  21. 21.
    Choi SW, Gu BH, Ramakrishna S, Park JM, Baek KH. Association between a single nucleotide polymorphism in MTHFR gene and polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2009;145:85–8. doi: 10.1016/j.ejogrb.2009.04.013.CrossRefPubMedGoogle Scholar
  22. 22.
    Moran LJ, Hutchison SK, Norman RJ, Teede HJ. Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2011:CD007506; doi: 10.1002/14651858.CD007506.pub3.
  23. 23.
    Chae SJ, Kim JJ, Choi YM, Hwang KR, Jee BC, Ku SY, et al. Clinical and biochemical characteristics of polycystic ovary syndrome in Korean women. Hum Reprod. 2008;23:1924–31. doi: 10.1093/humrep/den239.CrossRefPubMedGoogle Scholar
  24. 24.
    Matarese G, De Placido G, Nikas Y, Alviggi C. Pathogenesis of endometriosis: natural immunity dysfunction or autoimmune disease? Trends Mol Med. 2003;9:223–8. doi: 10.1016/S1471-4914(03)00051-0.CrossRefPubMedGoogle Scholar
  25. 25.
    Haller K, Mathieu C, Rull K, Matt K, Bene MC, Uibo R. IgG, IgA and IgM antibodies against FSH: serological markers of pathogenic autoimmunity or of normal immunoregulation? Am J Reprod Immunol. 2005;54:8. doi: 10.1111/j.1600-0897.2005.00306.x.CrossRefGoogle Scholar
  26. 26.
    Hughes C, Elgasim M, Layfield R, Atiomo W. Genomic and post-genomic approaches to polycystic ovary syndrome—progress so far: mini review. Hum Reprod. 2006;21:10. doi: 10.1093/humrep/del222.CrossRefGoogle Scholar
  27. 27.
    Urbanek M, Woodroffe A, Ewens KG, Diamanti-Kandarakis E, Legro RS, Strauss 3rd JF, et al. Candidate gene region for polycystic ovary syndrome on chromosome 19p13.2. J Clin Endocrinol Metab. 2005;90:7. doi: 10.1210/jc.2005-0622.CrossRefGoogle Scholar
  28. 28.
    Legro RS, Bentley-Lewis R, Driscoll D, Wang SC, Dunaif A. Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity. J Clin Endocrinol Metab. 2002;87:2128–33.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wu R, Fujii S, Ryan NK, Van der Hoek KH, Jasper MJ, Sini I, et al. Ovarian leukocyte distribution and cytokine/chemokine mRNA expression in follicular fluid cells in women with polycystic ovary syndrome. Hum Reprod. 2007;22:527–35. doi: 10.1093/humrep/del371.CrossRefPubMedGoogle Scholar
  30. 30.
    Silverman ES, Palmer LJ, Subramaniam V, Hallock A, Mathew S, Vallone J, et al. Transforming growth factor-beta1 promoter polymorphism C-509T is associated with asthma. Am J Respir Crit Care Med. 2004;169:214–9. doi: 10.1164/rccm.200307-973OC.CrossRefPubMedGoogle Scholar
  31. 31.
    Crilly A, Hamilton J, Clark CJ, Jardine A, Madhok R. Analysis of transforming growth factor beta1 gene polymorphisms in patients with systemic sclerosis. Ann Rheum Dis. 2002;61:678–81.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Dunning AM, Ellis PD, McBride S, Kirschenlohr HL, Healey CS, Kemp PR, et al. A transforming growth factorbeta1 signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer. Cancer Res. 2003;63:2610–5.PubMedGoogle Scholar
  33. 33.
    Thys M, Schrauwen I, Vanderstraeten K, Janssens K, Dieltjens N, Van Den Bogaert K, et al. The coding polymorphism T263I in TGF-beta1 is associated with otosclerosis in two independent populations. Hum Mol Genet. 2007;16:2021–30. doi: 10.1093/hmg/ddm150.CrossRefPubMedGoogle Scholar
  34. 34.
    Park JH, Li L, Baek KH. Study of the association of the T869C polymorphism of the transforming growth factor-beta1 gene with polycystic ovary syndrome. Mol Med Rep. 2015;12:4560–5. doi: 10.3892/mmr.2015.3896.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Eun Youn Roh
    • 1
    • 2
  • Jong Hyun Yoon
    • 1
    • 2
  • Eun Young Song
    • 2
  • Jin Ju Kim
    • 3
  • Kyu Ri Hwang
    • 4
  • Soo Hyun Seo
    • 1
    • 2
  • Sue Shin
    • 1
    • 2
    Email author
  1. 1.Department of Laboratory MedicineSeoul National University Boramae Medical CenterSeoulRepublic of Korea
  2. 2.Department of Laboratory MedicineSeoul National University College of MedicineSeoulRepublic of Korea
  3. 3.Department of Obstetrics and GynecologySeoul National University Healthcare System Gangnam CenterSeoulRepublic of Korea
  4. 4.Departments of Obstetrics and GynecologySeoul National University Boramae Medical CenterSeoulRepublic of Korea

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