Skip to main content
Log in

Associations between TNF-α and interleukin gene polymorphisms with polycystic ovary syndrome risk: a systematic review and meta-analysis

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Background

The associations between TNF-α and Interleukin gene polymorphisms and polycystic ovary syndrome (PCOS) risk have been studied in numerous epidemiological studies, but the results remain controversial. To investigate whether these polymorphisms facilitate susceptibility to PCOS, we conducted a comprehensive systematic review and meta-analysis.

Methods

PubMed, Embase, Web of Science, Medline, CNKI, and Google Scholar were searched to obtain the genetic association studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Odds ratios (OR) with corresponding 95 % confidence intervals (CI) were used to assess the strengths of the associations. Funnel plots and Egger’s tests were performed to test for possible publication bias. All statistical analyses were performed using Review Manager 5.2 and STATA11.0.

Results

Eighteen articles were included in the final meta-analysis. The studies involved the following polymorphisms: TNF-α -308G > A, TNF-α -805C > T, TNF-α -1031 T > C, IL-1A -889C > T, IL-1B -511C > T, IL-1B +3953 T > C, IL-6 -174G > C, IL-10 -819C > T, IL-10 -1082A > G, IL-18 -607C > A, and IL-18 -137G > C. Our results show a significant association between PCOS risk and the TNF-α -1031 T > C polymorphism (For TC + CC vs. TT: OR = 2.09, 95 % CI = 1.58–2.76, p < 0.0001. For C allele vs. T allele: OR = 1.67, 95 % CI = 1.33–2.09, p < 0.0001) and between PCOS risk and the IL-6 -174G > C polymorphism (For CC + GC vs. GG: OR = 0.49, 95 % CI = 0.25–0.95, p = 0.03. For CC vs. GG: OR = 0.48, 95 % CI = 0.28–0.80, p = 0.005. For C vs. G: OR = 0.60, 95 % CI = 0.42–0.87, p = 0.007). No associations were found with the other genetic models.

Conclusion

The results of the meta-analysis suggest positive associations between the TNF-α -1031 T > C and IL-6 -174G > C polymorphisms and the risk of PCOS. No associations are found between PCOS risk and the TNF-α -308G > A, TNF-α -805C > T, IL-1A -889C > T, IL-1B -511C > T, IL-1B +3953C > T, IL-10 -819C > T, IL-10 -1082 A > G, IL-18 -607C > A, and IL-18 -137G > C polymorphisms. However, due to the heterogeneity and low quality of the studies related to PCOS polymorphisms in the meta-analysis, the results should be interpreted with caution. Future multi-ethnicity studies of homogeneous populations of PCOS patients with larger sample sizes and well-matched controls are needed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011;7(4):219–31. doi:10.1038/nrendo.2010.217.

    Article  CAS  PubMed  Google Scholar 

  2. Brassard M, AinMelk Y, Baillargeon JP. Basic infertility including polycystic ovary syndrome. Med Clin N Am. 2008;92(5):1163–92. doi:10.1016/j.mcna.2008.04.008.

    Article  CAS  PubMed  Google Scholar 

  3. Mani H, Levy MJ, Davies MJ, Morris DH, Gray LJ, Bankart J, et al. Diabetes and cardiovascular events in women with polycystic ovary syndrome: a 20-year retrospective cohort study. Clin Endocrinol (Oxf). 2013;78(6):926–34. doi:10.1111/cen.12068.

    Article  Google Scholar 

  4. Dokras A. Cardiovascular disease risk factors in polycystic ovary syndrome. Semin Reprod Med. 2008;26(1):39–44. doi:10.1055/s-2007-992923.

    Article  CAS  PubMed  Google Scholar 

  5. Ojeda-Ojeda M, Murri M, Insenser M, Escobar-Morreale HF. Mediators of low-grade chronic inflammation in polycystic ovary syndrome (PCOS). Curr Pharm Des. 2013;19(32):5775–91.

    Article  CAS  PubMed  Google Scholar 

  6. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5. doi:10.1007/s10654-010-9491-z.

    Article  PubMed  Google Scholar 

  7. 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(12):1541–6. doi:10.1007/s10815-013-0111-1.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Xia YH, Yao L, Zhang ZX. Correlation between IL-1beta, IL-1Ra gene polymorphism and occurrence of polycystic ovary syndrome infertility. Asian Pac J Trop Med. 2013;6(3):232–6. doi:10.1016/S1995-7645(13)60030-9.

    Article  CAS  PubMed  Google Scholar 

  9. Kosova G, Urbanek M. Genetics of the polycystic ovary syndrome. Mol Cell Endocrinol. 2013;373(1–2):29–38. doi:10.1016/j.mce.2012.10.009.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Deligeoroglou E, Vrachnis N, Athanasopoulos N, Iliodromiti Z, Sifakis S, Iliodromiti S, et al. Mediators of chronic inflammation in polycystic ovarian syndrome. Gynecol Endocrinol. 2012;28(12):974–8. doi:10.3109/09513590.2012.683082.

    Article  CAS  PubMed  Google Scholar 

  11. Yang Y, Qiao J, Li MZ. Correlation between interleukin-1 and the obesity of polycystic ovary syndrome. Zhonghua Fu Chan Ke Za Zhi. 2012;47(1):9–13.

    PubMed  Google Scholar 

  12. 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(1):51–5. doi:10.1016/j.ejogrb.2011.12.008.

    Article  CAS  PubMed  Google Scholar 

  13. Kawamura S, Maesawa C, Nakamura K, Nakayama K, Morita M, Hiruma Y, et al. Predisposition for borderline personality disorder with comorbid major depression is associated with that for polycystic ovary syndrome in female Japanese population. Neuropsychiatr Dis Treat. 2011;7:655–62. doi:10.2147/NDT.S25504.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Lin YS, Tsai SJ, Lin MW, Yang CT, Huang MF, Wu MH. Interleukin-6 as an early chronic inflammatory marker in polycystic ovary syndrome with insulin receptor substrate-2 polymorphism. Am J Reprod Immunol. 2011;66(6):527–33. doi:10.1111/j.1600-0897.2011.01059.x.

    Article  CAS  PubMed  Google Scholar 

  15. Yang Y, Qiao J, Li MZ. Association of polymorphisms of interleukin-18 gene promoter region with polycystic ovary syndrome in chinese population. Reprod Biol Endocrinol. 2010;8:125. doi:10.1186/1477-7827-8-125.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Mu Y, Liu J, Wang B, Wen Q, Wang J, Yan J, et al. Interleukin 1 beta (IL-1beta) promoter C [−511] T polymorphism but not C [+3953] T polymorphism is associated with polycystic ovary syndrome. Endocrine. 2010;37(1):71–5. doi:10.1007/s12020-009-9268-x.

    Article  CAS  PubMed  Google Scholar 

  17. Vural P, Degirmencioglu S, Saral NY, Akgul C. Tumor necrosis factor alpha (−308), interleukin-6 (−174) and interleukin-10 (−1082) gene polymorphisms in polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2010;150(1):61–5. doi:10.1016/j.ejogrb.2010.02.010.

    Article  CAS  PubMed  Google Scholar 

  18. Yang Y, Qiao J, Tang RX, Li MZ. Genotype and haplotype determination of interleukin (IL) 1 beta (g. -511C > T and g. +3954C > T) and IL-1RN in polycystic ovary syndrome. Fertil Steril. 2010;94(1):384–6. doi:10.1016/j.fertnstert.2009.09.042.

    Article  CAS  PubMed  Google Scholar 

  19. Erdogan M, Karadeniz M, Berdeli A, Tamsel S, Yilmaz C. The relationship of the interleukin-6–174 G > C gene polymorphism with cardiovascular risk factors in Turkish polycystic ovary syndrome patients. Int J Immunogenet. 2009;36(5):283–8. doi:10.1111/j.1744-313X.2009.00867.x.

    Article  CAS  PubMed  Google Scholar 

  20. Wang B, Zhou S, Wang J, Liu J, Ni F, Liu C, et al. Lack of association between interleukin-1a gene (IL-1a) C (−889) T variant and polycystic ovary syndrome in Chinese women. Endocrine. 2009;35(2):198–203. doi:10.1007/s12020-009-9152-8.

    Article  CAS  PubMed  Google Scholar 

  21. Erdogan M, Karadeniz M, Berdeli A, Alper G, Caglayan O, Yilmaz C. The relationship of the interleukin-6–174 G > C gene polymorphism with oxidative stress markers in Turkish polycystic ovary syndrome patients. J Endocrinol Investig. 2008;31(7):624–9.

    Article  CAS  Google Scholar 

  22. Karadeniz M, Erdogan M, Zengi A, Tamsel S, Berdeli A, Saygili F, et al. Polymorphism of the interleukin-10 gene in polycystic ovary syndrome. Int J Immunogenet. 2008;35(2):119–23. doi:10.1111/j.1744-313X.2007.00746.x.

    Article  CAS  PubMed  Google Scholar 

  23. Kolbus A, Walch K, Szabo L, Huber JC, Nagele F, Unfried G. A polymorphism of the interleukin 1 receptor antagonist is not associated with polycystic ovary syndrome in Caucasian women. Fertil Steril. 2006;85(2):523–5. doi:10.1016/j.fertnstert.2005.07.1317.

    Article  CAS  PubMed  Google Scholar 

  24. Mohlig M, Spranger J, Osterhoff M, Ristow M, Pfeiffer AF, Schill T, et al. The polycystic ovary syndrome per se is not associated with increased chronic inflammation. Eur J Endocrinol. 2004;150(4):525–32.

    Article  PubMed  Google Scholar 

  25. Kolbus A, Walch K, Nagele F, Wenzl R, Unfried G, Huber JC. Interleukin-1 alpha but not interleukin-1 beta gene polymorphism is associated with polycystic ovary syndrome. J Reprod Immunol. 2007;73(2):188–93. doi:10.1016/j.jri.2006.08.002.

    Article  CAS  PubMed  Google Scholar 

  26. Walch K, Grimm C, Zeillinger R, Huber JC, Nagele F, Hefler LA. A common interleukin-6 gene promoter polymorphism influences the clinical characteristics of women with polycystic ovary syndrome. Fertil Steril. 2004;81(6):1638–41. doi:10.1016/j.fertnstert.2004.01.021.

    Article  CAS  PubMed  Google Scholar 

  27. Deepika ML, Reddy KR, Yashwanth A, Rani VU, Latha KP, Jahan P. TNF-alpha haplotype association with polycystic ovary syndrome - a South Indian study. J Assist Reprod Genet. 2013;30(11):1493–503. doi:10.1007/s10815-013-0080-4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Yun JH, Choi JW, Lee KJ, Shin JS, Baek KH. The promoter −1031(T/C) polymorphism in tumor necrosis factor-alpha associated with polycystic ovary syndrome. Reprod Biol Endocrinol. 2011;9:131. doi:10.1186/1477-7827-9-131.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Korhonen S, Romppanen EL, Hiltunen M, Mannermaa A, Punnonen K, Hippelainen M, et al. Lack of association between C-850 T polymorphism of the gene encoding tumor necrosis factor-alpha and polycystic ovary syndrome. Gynecol Endocrinol. 2002;16(4):271–4.

    Article  CAS  PubMed  Google Scholar 

  30. Peral B, San Millan JL, Castello R, Moghetti P, Escobar-Morreale HF. Comment: the methionine 196 arginine polymorphism in exon 6 of the TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary syndrome and hyperandrogenism. J Clin Endocrinol Metab. 2002;87(8):3977–83. doi:10.1210/jcem.87.8.8715.

    Article  CAS  PubMed  Google Scholar 

  31. Mao W, Yu L, Chen Y. Study on the relationship between a polymorphism of tumor necrosis factor-alpha gene and the pathogenesis of polycystic ovary syndrome. Zhonghua Fu Chan Ke Za Zhi. 2000;35(9):536–9.

    CAS  PubMed  Google Scholar 

  32. Milner CR, Craig JE, Hussey ND, Norman RJ. No association between the −308 polymorphism in the tumour necrosis factor alpha (TNFalpha) promoter region and polycystic ovaries. Mol Hum Reprod. 1999;5(1):5–9.

    Article  CAS  PubMed  Google Scholar 

  33. Xu X, Du C, Zheng Q, Peng L, Sun Y. Effect of metformin on serum interleukin-6 levels in polycystic ovary syndrome: a systematic review. BMC Womens Health. 2014;14:93. doi:10.1186/1472-6874-14-93.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Dai L, Liu D, Guo H, Wang Y, Bai Y. Association between polymorphism in the promoter region of Interleukin 6 (−174 G/C) and risk of Alzheimer’s disease: a meta-analysis. J Neurol. 2012;259(3):414–9. doi:10.1007/s00415-011-6164-0.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

No funding was provided for the analysis.

Conflict of interest

None Declared.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Haijing Wu.

Additional information

Capsule The twelve SNPs for TNF-α and Interleukin genes: TNF-α -1031T > C and IL-6 -174G > C are associated with PCOS risk, and no associations are found in TNF-α -308G > A, TNF-α -805C > T, IL-1A -889C > T, IL-1B -511C > T, IL-1B +3953C > T, IL-10 -819C > T, IL-10 -1082 A > G, IL-18 -607C > A, and IL-18 -137G > C polymorphisms.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 71 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, H., Yu, K. & Yang, Z. Associations between TNF-α and interleukin gene polymorphisms with polycystic ovary syndrome risk: a systematic review and meta-analysis. J Assist Reprod Genet 32, 625–634 (2015). https://doi.org/10.1007/s10815-015-0449-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-015-0449-7

Keywords

Navigation