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Association between IL-6 −174 G/C, IL-6 −634 G/C, and IFN-γ +874 A/T polymorphisms and susceptibility to recurrent pregnancy loss: a meta-analysis

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

Abstract

Objective

The aim of this study was to determine whether interleukin-6 (IL-6) −174 G/C, IL-6 −634 G/C, and interferon-γ (IFN-γ) +874 A/T polymorphisms are associated with susceptibility to recurrent pregnancy loss (RPL).

Methods

We conducted a literature search using PubMed and EMBASE databases and performed a meta-analysis using fixed- or random-effects models.

Results

A total of 15 articles met the study inclusion criteria. When all study subjects were considered together, meta-analysis showed no association between RPL and the IL-6 −174 GG + GC genotype (odds ratio [OR] = 0.794, 95 % confidence interval [CI] = 0.542–1.163, p = 0.236). However, stratification of the data by ethnicity indicated an association between this genotype and RPL in non-Caucasians (OR = 0.528, 95 % CI = 0.302–0.925, p = 0.028), but not in Caucasian populations. Moreover, meta-analysis revealed an association between RPL and the IL-6 −634 GG + GC genotype in all study subjects (OR = 0.556, 95 % CI = 0.383–0.806, p = 0.002), while stratification by ethnicity revealed a negative association between this genotype and RPL in Asian (OR = 0.545, 95 % CI = 0.371–0.800, p = 0.002) but not Middle Eastern populations. Furthermore, a relationship between the IFN-γ +874 A allele and RPL was identified in non-Caucasians (OR = 1.403, 95 % CI = 1.133–1.734, p = 0.002), but not in Caucasians.

Conclusions

This meta-analysis demonstrates that IL-6 −174 G/C, IL-6 −634 G/C, and IFN-γ +874 A/T polymorphisms are associated with susceptibility to RPL, particularly in non-Caucasians.

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References

  1. Stirrat GM. Recurrent miscarriage I: definition and epidemiology. Lancet. 1990;336(8716):673–5.

    Article  CAS  PubMed  Google Scholar 

  2. Clark DA, Chaouat G, Wong K, Gorczynski RM, Kinsky R. Review article: tolerance mechanisms in pregnancy: a reappraisal of the role of class I paternal MHC antigens*. Am J Reprod Immunol. 2010;63(2):93–103.

    Article  CAS  PubMed  Google Scholar 

  3. Saini V, Arora S, Yadav A, Bhattacharjee J. Cytokines in recurrent pregnancy loss. Clin Chim Acta. 2011;412(9):702–8.

    Article  CAS  PubMed  Google Scholar 

  4. Kwak‐Kim J, Park JC, Ahn HK, Kim JW, Gilman‐Sachs A. Review article: immunological modes of pregnancy loss. Am J Reprod Immunol. 2010;63(6):611–23.

    Article  PubMed  Google Scholar 

  5. Raghupathy R (ed) Pregnancy: success and failure within the Th1/Th2/Th3 paradigm. Seminars in immunology. Elsevier;2001.

  6. Makhseed M, Raghupathy R, Azizieh F, Omu A, Al-Shamali E, Ashkanani L. Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions. Hum Reprod. 2001;16(10):2219–26.

    Article  CAS  PubMed  Google Scholar 

  7. Yui J, Garcia-Lloret M, Wegmann TG, Guilbert LJ. Cytotoxicity of tumour necrosis factor-alpha and gamma-interferon against primary human placental trophoblasts. Placenta. 1994;15(8):819–35.

    Article  CAS  PubMed  Google Scholar 

  8. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro-and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta (BBA)-Mol Cell Res. 2011;1813(5):878–88.

    Article  CAS  Google Scholar 

  9. Raghupathy R, Makhseed M, Azizieh F, Hassan N, Al-Azemi M, Al-Shamali E. Maternal Th1-and Th2-type reactivity to placental antigens in normal human pregnancy and unexplained recurrent spontaneous abortions. Cell Immunol. 1999;196(2):122–30.

    Article  CAS  PubMed  Google Scholar 

  10. Daher S, Denardi KDAG, Blotta MHSL, et al. Cytokines in recurrent pregnancy loss. J Reprod Immunol. 2004;62(1):151–7.

    Article  CAS  PubMed  Google Scholar 

  11. Morse HR, Olomolaiye OO, Wood NA, Keen LJ, Bidwell JL. Induced heteroduplex genotyping of TNF-alpha, IL-1beta, IL-6 and IL-10 polymorphisms associated with transcriptional regulation. Cytokine. 1999;11(10):789–95.

    Article  CAS  PubMed  Google Scholar 

  12. Hulkkonen J, Pertovaara M, Antonen J, Pasternack A, Hurme M. Elevated interleukin-6 plasma levels are regulated by the promoter region polymorphism of the IL6 gene in primary Sjogren’s syndrome and correlate with the clinical manifestations of the disease. Rheumatology (Oxford). 2001;40(6):656–61.

    Article  CAS  Google Scholar 

  13. Pravica V, Perrey C, Stevens A, Lee J-H, Hutchinson IV. A single nucleotide polymorphism in the first intron of the human IFN-γ gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-γ production. Hum Immunol. 2000;61(9):863–6.

    Article  CAS  PubMed  Google Scholar 

  14. C LB, V ER. Interleukin-6 and interleukin-10 gene polymorphisms and recurrent pregnancy loss in Romanian population. Iranian journal of reproductive medicine. 2014;12(9):617–22.

  15. Demirturk F, Ates O, Gunal O, Bozkurt N, Aysal T, Nacar MC. IL-6 gene promoter polymorphisms: genetic susceptibility to recurrent pregnancy loss. Bratisl Lek Listy. 2014;115(8):479–82.

    CAS  PubMed  Google Scholar 

  16. Bahadori M, Zarei S, Zarnani AH, et al. IL-6, IL-10 and IL-17 gene polymorphisms in Iranian women with recurrent miscarriage. Iran J Immunol: IJI. 2014;11(2):97–104.

    PubMed  Google Scholar 

  17. Parveen F, Shukla A, Agarwal S. Cytokine gene polymorphisms in northern Indian women with recurrent miscarriages. Fertil Steril. 2013;99(2):433–40.

    Article  CAS  PubMed  Google Scholar 

  18. von Linsingen R, Bompeixe EP, Bicalho MG. A case-control study in IL6 and TGFB1 gene polymorphisms and recurrent spontaneous abortion in southern Brazilian patients. Am J Reprod Immunol. 2005;53(2):94–9.

    Article  Google Scholar 

  19. Saijo Y, Sata F, Yamada H, Kondo T, Kato EH, Kishi R. Single nucleotide polymorphisms in the promoter region of the interleukin-6 gene and the risk of recurrent pregnancy loss in Japanese women. Fertil Steril. 2004;81(2):374–8.

    Article  CAS  PubMed  Google Scholar 

  20. Daher S, Shulzhenko N, Morgun A, et al. Associations between cytokine gene polymorphisms and recurrent pregnancy loss. J Reprod Immunol. 2003;58(1):69–77.

    Article  CAS  PubMed  Google Scholar 

  21. Unfried G, Bocskor S, Endler G, Nagele F, Huber JC, Tempfer CB. A polymorphism of the interleukin-6 gene promoter and idiopathic recurrent miscarriage. Hum Reprod. 2003;18(2):267–70.

    Article  CAS  PubMed  Google Scholar 

  22. Alkhuriji AF, Alhimaidi AR, Babay ZA, Wary AS. The relationship between cytokine gene polymorphism and unexplained recurrent spontaneous abortion in Saudi females. Saudi Med J. 2013;34(5):484–9.

    PubMed  Google Scholar 

  23. Ma X, Xu LJ, Wang J, Xian MM, Liu M. Association of IL-1beta and IL-6 gene polymorphisms with recurrent spontaneous abortion in a Chinese Han population. Int J Immunogenet. 2012;39(1):15–9.

    Article  CAS  PubMed  Google Scholar 

  24. El-Hamid SA, El-Khayat W. Relationship of the protein Z intron F G79A and IL6 C634G gene polymorphisms with the risk of recurrent pregnancy loss in Egyptian women. J Investig Med Off Publ Am Fed Clin Res. 2011;59(4):655–60.

    CAS  Google Scholar 

  25. Zastavna D, Sosnina K, Terpylyak O, et al. Cytogenetic and immunogenetic analysis of recurrent pregnancy loss in women. Tsitol Genet. 2014;48(4):44–50.

    CAS  PubMed  Google Scholar 

  26. Kamali-Sarvestani E, Zolghadri J, Gharesi-Fard B, Sarvari J. Cytokine gene polymorphisms and susceptibility to recurrent pregnancy loss in Iranian women. J Reprod Immunol. 2005;65(2):171–8.

    Article  CAS  PubMed  Google Scholar 

  27. Prigoshin N, Tambutti M, Larriba J, Gogorza S, Testa R. Cytokine gene polymorphisms in recurrent pregnancy loss of unknown cause. Am J Reprod Immunol. 2004;52(1):36–41.

    Article  PubMed  Google Scholar 

  28. Babbage SJ, Arkwright PD, Vince GS, et al. Cytokine promoter gene polymorphisms and idiopathic recurrent pregnancy loss. J Reprod Immunol. 2001;51(1):21–7.

    Article  CAS  PubMed  Google Scholar 

  29. Lee YH, Bae SC, Choi SJ, Ji JD, Song GG. Associations between vitamin D receptor polymorphisms and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis. Mol Biol Rep.38(6):3643–51.

  30. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Associations between osteoprotegerin polymorphisms and bone mineral density: a meta-analysis. Mol Biol Rep.37(1):227–34.

  31. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis. Rheumatol Int. 2010;30(3):357–63.

    Article  CAS  PubMed  Google Scholar 

  32. Davey Smith G, Egger M. Meta-analyses of randomised controlled trials. Lancet. 1997;350(9085):1182.

    Article  CAS  PubMed  Google Scholar 

  33. Egger M, Smith GD, Phillips AN. Meta-analysis: principles and procedures. BMJ. 1997;315(7121):1533–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.

    Article  CAS  PubMed  Google Scholar 

  35. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.

    Article  PubMed  Google Scholar 

  36. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Bombell S, McGuire W. Cytokine polymorphisms in women with recurrent pregnancy loss: meta-analysis. Aust NZ J Obstet Gynaecol. 2008;48(2):147–54.

    Article  Google Scholar 

  38. Choi YK, Kwak-Kim J. Cytokine gene polymorphisms in recurrent spontaneous abortions: a comprehensive review. Am J Reprod Immunol. 2008;60(2):91–110.

    Article  CAS  PubMed  Google Scholar 

  39. Medica I, Ostojic S, Pereza N, Kastrin A, Peterlin B. Association between genetic polymorphisms in cytokine genes and recurrent miscarriage—a meta-analysis. Reprod Biomed Online. 2009;19(3):406–14.

    Article  CAS  PubMed  Google Scholar 

  40. Lim CS, Zheng S, Kim YS, et al. The −174 G to C polymorphism of interleukin-6 gene is very rare in Koreans. Cytokine. 2002;19(1):52–4.

    Article  CAS  PubMed  Google Scholar 

  41. Zhai R, Liu G, Yang C, Huang C, Wu C, Christiani DC. The G to C polymorphism at -174 of the interleukin -6 gene is rare in a Southern Chinese population. Pharmacogenet Genomics. 2001;11(8):699–701.

    Article  CAS  Google Scholar 

  42. Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998;102(7):1369–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Medica I, Ostojic S, Pereza N, Kastrin A, Peterlin B. Association between genetic polymorphisms in cytokine genes and recurrent miscarriage—a meta-analysis. Reprod Biomed Online. 2009;19(3):406–14.

    Article  CAS  PubMed  Google Scholar 

  44. Bombell S, McGuire W. Cytokine polymorphisms in women with recurrent pregnancy loss: meta‐analysis. Aust NZ J Obstet Gynaecol. 2008;48(2):147–54.

    Article  Google Scholar 

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Acknowledgments

This research received no specific grant from any public, commercial, or not-for-profit sectors funding agency.

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The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 73, Inchon-ro, Seongbuk-gu, Seoul, 136-705, South Korea

    Young Ho Lee, Sung Jae Choi & Jong Dae Ji

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  1. Young Ho Lee
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Correspondence to Young Ho Lee.

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Capsule

Our meta-analysis demonstrates that IL-6 −174 G/C, −634 G/C, and IFN-γ +874 A/Tpolymorphisms are associated with susceptibility to RPL, particularly in non-Caucasians.

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Lee, Y.H., Choi, S.J. & Ji, J.D. Association between IL-6 −174 G/C, IL-6 −634 G/C, and IFN-γ +874 A/T polymorphisms and susceptibility to recurrent pregnancy loss: a meta-analysis. J Assist Reprod Genet 32, 1421–1427 (2015). https://doi.org/10.1007/s10815-015-0566-3

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  • DOI: https://doi.org/10.1007/s10815-015-0566-3

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