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Relationship between HLA-G polymorphism and susceptibility to recurrent miscarriage: A meta-analysis of non-family-based studies

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

Abstract

Purpose

The HLA-G 14-bp insertion/deletion polymorphism had been inconsistently associated with recurrent miscarriage (RM) risk. We examined the association by performing a meta-analysis.

Methods

Eligible articles were searched in PubMed, EMBASE and CNKI without language limitation. We included all the articles about two or more miscarriages associated with HLA-G 14-bp polymorphism. The odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of associations. Statistical analyses were performed by the STATA10.0 software.

Results

17 studies were included, representing 1786 cases and 1574 controls. The current meta-analysis showed that 14-bp polymorphism was not associated with RM risk in all genetic models and allele contrast(+14 bp vs. −14 bp: OR = 1.13; 95 % CI, 0.96,1.32; +14 bp/+14 bp vs. −14 bp/−14 bp: OR = 1.16, 95 % CI, 0.85, 1.59; +14 bp/−14 bp vs. −14 bp/−14 bp: OR = 1.21, 95 % CI, 0.92,1.58; dominant model: OR = 1.33; 95 % CI, 0.99,1.78; recessive model: OR = 1.06; 95 % CI, 0.79,1.43). Moreover, a significant heterogeneity was evident across studies. On the other hand, the subgroup analysis demonstrated that there was a significant association between HLA-G 14-bp polymorphism and patients with three or more miscarriages(+14 bp vs. −14 bp: OR = 1.27; 95 % CI, 1.04, 1.55; dominant model: OR = 1.52; 95 % CI, 1.16, 1.99; and model +14 bp/−14 bp versus −14 bp/−14 bp: OR = 1.51; 95 % CI, 1.15, 1.97;).

Conclusions

Our comprehensive meta-analysis indicated that there was insufficient evidence to demonstrate a conclusive association between the HLA-G 14-bp insertion/deletion polymorphism and the risk of RM. But HLA-G 14-bp insertion/deletion polymorphic variation was associated with RM risk in patients with three or more miscarriages. Larger and well-designed studies may eventually provide a better, comprehensive understanding of the association between the HLA-G 14-bp insertion/deletion polymorphism and RM in the future.

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References

  1. Mishell Jr DR. Recurrent abortion. J Reprod Med. 1993;38:250–9.

    PubMed  Google Scholar 

  2. Royal College of Obstetricians and Gynaecologists. The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage. In: Green-top Guideline No17. London: Royal College of Obstetricians and Gynaecologists; 2011.

    Google Scholar 

  3. American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98:1103–11.

    Article  Google Scholar 

  4. Jaslow CR, Carney JL, Kutteh WH. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses. Fertil Steril. 2010;93:1234–43.

    Article  CAS  PubMed  Google Scholar 

  5. Stephenson M. Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril. 1996;66:24–9.

    CAS  PubMed  Google Scholar 

  6. Ren AG, Wang J. Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: A meta-analysis. Fertil Steril. 2006;86:1716–22.

    Article  CAS  PubMed  Google Scholar 

  7. Pandey MK, Rani R, Agrawal S. An update in recurrent spontaneous abortion. Arch Gynecol Obstet. 2005;272(2):95–108.

    Article  CAS  PubMed  Google Scholar 

  8. Trowsdale J, Betz AG. Mother’s little helpers: mechanisms of maternal–fetal tolerance. Nat Immunol. 2006;7:241–6.

    Article  CAS  PubMed  Google Scholar 

  9. Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMars R. A class I antigen HLA-G, expressed in human trophoblasts. Science. 1990;248:220–3.

    Article  CAS  PubMed  Google Scholar 

  10. Goldman-Wohl DS, Ariel I, Greenfield C, Hochner-Celnikier D, Cross J, Fisher S, et al. Lack of human leukocyte antigen-G expression in extravillous trophoblasts is associated with pre-eclampsia. Mol Hum Reprod. 2000;6:88–95.

    Article  CAS  PubMed  Google Scholar 

  11. Hunt JS, Morales PJ, Pace JL, Fazleabas AT, Langat DK. A commentary on gestational programming and functions of HLA-G in pregnancy. Placenta. 2007;21:S57–63.

    Article  CAS  Google Scholar 

  12. Jassem RM, Shani WS, Loisel DA, Sharief M, Billstrand C, Ober C. HLA-G polymorphisms and soluble HLA-G protein levels in women with recurrent pregnancy loss from Basrah province in Iraq. Hum Immunol. 2012;73:811–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Vercammen MJ, Verloes A, Van de Velde H, Haentjens P. Accuracy of soluble human leukocyte antigen-G for predicting pregnancy among women undergoing infertility treatment: meta-analysis. Hum Reprod Update. 2008;14:209–18.

    Article  CAS  PubMed  Google Scholar 

  14. Consiglio CR, Veit TD, Monticielo OA, Mucenic T, Xavier RM, Brenol JC, et al. Association of the HLA-G gene +3142C > G polymorphism with systemic lupus erythematosus. Tissue Antigens. 2011;77:540–5.

    Article  CAS  PubMed  Google Scholar 

  15. Hviid TV, Rizzo R, Christiansen OB, Melchiorri L, Lindhard A, Baricordi OR. HLA-G and IL-10 in plasma in relation to HLA-G genotype and polymorphisms. Immunogenetics. 2004;56:135–41.

    Article  CAS  PubMed  Google Scholar 

  16. Tan V, Randall G, Fan V, Camoretti-Mercado B, Brockman-Schneider R, Pan L, et al. Allele-specific targeting of microRNAs to HLA-G and risk of asthma. Am J Hum Genet. 2007;81:829–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Yan WH, Lin V, Chen XJ, Dai MZ, Gan LH, Zhou MY, et al. Association of the maternal 14-bp insertion polymorphism in the HLA-G gene in women with recurrent spontaneous abortions. Tissue Antigens. 2006;68:521–3.

    Article  CAS  PubMed  Google Scholar 

  18. Hviid TV, Christiansen OB. Linkage disequilibrium between human leukocyte antigen (HLA) class II and HLA-G - possible implications for human reproduction and autoimmune disease. Hum Immunol. 2005;66:688–99.

    Article  CAS  PubMed  Google Scholar 

  19. Hiby SE, King A, Sharkey A, Loke YW. Molecular studies of trophoblast HLA-G: polymorphism, isoforms, imprinting and expression in preimplantation embryo. Tissue Antigens. 1999;53:1–13.

    Article  CAS  PubMed  Google Scholar 

  20. Hviid TV, Hylenius S, Rorbye C, Nielsen LG. HLA-G allelic variants are associated with differences in the HLA-G mRNA isoform profile and HLA-G mRNA levels. Immunogenetics. 2003;55:63–79.

    CAS  PubMed  Google Scholar 

  21. Rousseau P, Le Discorde M, Mouillot G, Marcou C, Carosella ED, Moreau P. The 14 bp deletion-insertion polymorphism in the 3′ UT region of the HLA-G gene influences HLA-G mRNA stability. Hum Immunol. 2003;64:1005–10.

    Article  CAS  PubMed  Google Scholar 

  22. Rizzo R, Hviid TV, Stignani M, Balboni A, Grappa MT, Melchiorri L, et al. The HLA-G genotype is associated with IL-10 levels in activated PBMCs. Immunogenetics. 2005;57:172–81.

    Article  CAS  PubMed  Google Scholar 

  23. Wang X, Jiang W, Zhang D. Association of 14-bp insertion/deletion polymorphism of HLA-G gene with unexplained recurrent spontaneous abortion: a meta-analysis. Tissue Antigens. 2013;81:108–15.

    Article  CAS  PubMed  Google Scholar 

  24. Gong M, Long J, Liu Q, Deng HC. Association of the ADIPOQ rs17360539 and rs266729 polymorphisms with type 2 diabetes: a meta-analysis. Mol Cell Endocrinol. 2010;325:78–83.

    Article  CAS  PubMed  Google Scholar 

  25. Akhter A, Faridi RM, Das V, Pandey A, Naik S, Agrawal S. In vitro up-regulation of HLA-G using dexamethasone and hydrocortisone in first-trimester trophoblast cells of women experiencing recurrent miscarriage. Tissue Antigens. 2012;80:126–35.

    Article  CAS  PubMed  Google Scholar 

  26. Kano T, Mori T, Furudono M, Ishikawa H, Watanabe H, Kikkawa E, et al. Human leukocyte antigen may predict outcome of primary recurrent spontaneous abortion treated with paternal lymphocyte alloimmunization therapy. Am J Reprod Immunol. 2007;58:383–7.

    Article  PubMed  Google Scholar 

  27. Liu YD, Shao JC, Wang ZM, Jing YM, Hu DC. Relationship of polymorphism of HLA-G 14 bp and RSA in the Kunmin. China Healthc Front. 2008;3:4–5.

    Google Scholar 

  28. Su MT, Lin SH, Chen YC. Genetic association studies of angiogenesis- and vasoconstriction-related genes in women with recurrent pregnancy loss: a systematic review and meta-analysis. Hum Reprod Update. 2011;17:803–12.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  30. Wenquan N, Yue Q, Pingjin G, Dingliang Z. Association between angiotensin converting enzyme G2350A polymorphism and hypertension risk: a meta-analysis. J Renin-Angiotensin-Aldosterone Syst. 2011;12:8–14.

    Article  Google Scholar 

  31. Wu XY, Lu JJ, Zhang JX, Li H. The Bonferroni Method for Multiple Comparisons. J Evidence-Based Med. 2006;6:361–3. 374.

    Google Scholar 

  32. Xue SG, Yang JQ, Yao FJ, Xu LD, Fan LA. Study on the polymorphism of the 14 bp deletion of HLA-G allele in patients with recurrent spontaneous abortion of unknown origin and normal deliveries. Curr Immunol. 2006;26:318–21.

    CAS  Google Scholar 

  33. Li CQ, Zhang X, Bao WG, Ling AF, Yan WH. Association of the maternal 14-bp insertion polymorphism in the HLA-G gene in women with recurrent spontaneous abortions. Zhejiang Pract Med. 2009;14:449–50.

    Google Scholar 

  34. Hviid TV, Hylenius S, Lindhard A, Christiansen OB. Association between human leukocyte antigen-G genotype and success of in vitro fertilization and pregnancy outcome. Tissue Antigens. 2004;64:66–9.

    Article  CAS  PubMed  Google Scholar 

  35. Hviid TV, Hylenius S, Hoegh AM, Kruse C, Christiansen OB. HLA-G polymorphisms in couples with recurrent spontaneous abortions. Tissue Antigens. 2002;60:122–32.

    Article  CAS  PubMed  Google Scholar 

  36. Sosnina KO, Zastavna DV, Terpylyak OI. The role of HLA-G 14 base pairs insertion/deletion polymorphism in the genesis of human early reproductive losses. Tissue Antigens. 2012;80:83.

    Google Scholar 

  37. Larsen MH, Dahl M, Pass MB, Hviid TV, Christiansen OB, Bzorek M, et al. The non-classical human leukocyte antigen (HLA)-G in human reproduction and complications of pregnancy. Tissue Antigens. 2010;75:543–4.

    Article  Google Scholar 

  38. Da Graca BM, Dos Santos SJ. Sarturi P; HLA-G 14 bp/del genotypes in Brazilian couples with recurrent spontaneous abortions. Tissue Antigens. 2009;74:91–2.

    Google Scholar 

  39. Kolte AM, Steffensen R, Nielsen HS, Hviid TV, Christiansen OB. Study of the structure and impact of human leukocyte antigen (HLA)-G-A, HLA-G-B, and HLA-G-DRB1 haplotypes in families with recurrent miscarriage. Hum Immunol. 2010;71:482–8.

    Article  CAS  PubMed  Google Scholar 

  40. Christiansen OB, Kolte AM, Dahl M, Larsen EC, Steffensen R, Nielsen HS, et al. Maternal homozygocity for a 14 base pair insertion in exon 8 of the HLA-G gene and carriage of HLA class II alleles restricting HY immunity predispose to unexplained secondary recurrent miscarriage and low birth weight in children born to these patients. Hum Immunol. 2012;73:699–705.

    Article  CAS  PubMed  Google Scholar 

  41. Shankarkumar U, Shankarkumar A, Chedda Z, Ghosh K. Role of 14-bp deletion/insertion polymorphism in exon 8 of the HLA-G gene in recurrent spontaneous abortion patients. J Hum Reprod Sci. 2011;4:143–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Vargas RG, Sarturi PR, Mattar SB, Bompeixe EP, Silva Jdos S, Pirri A, et al. Association of HLA-G alleles and 3′ UTR 14 bp haplotypes with recurrent miscarriage in Brazilian couples. Hum Immunol. 2011;72:479–85.

    Article  CAS  PubMed  Google Scholar 

  43. Aruna M, Sirisha PV, Andal Bhaskar S, Tarakeswari S, Thangaraj K, Reddy BM. Role of 14-bp insertion/deletion polymorphism in HLA-G among Indian women with recurrent spontaneous abortions. Tissue Antigens. 2011;77:131–5.

    Article  CAS  PubMed  Google Scholar 

  44. Berger DS, Hogge WA, Barmada MM, Ferrell RE. Comprehensive analysis of HLA-G: implications for recurrent spontaneous abortion. Reprod Sci. 2010;17:331–8.

    Article  CAS  PubMed  Google Scholar 

  45. Zhu Y, Huo Z, Lai J, Li S, Jiao H, Dang J, et al. Case–control study of a HLA-G 14-bp insertion-deletion polymorphism in women with recurrent miscarriages. Scand J Immunol. 2010;71:52–4.

    Article  CAS  PubMed  Google Scholar 

  46. Suryanarayana V, Rao L, Kanakavalli M, Padmalatha V, Raseswari T, Deenadayal M, et al. Association between novel HLA-G genotypes and risk of recurrent miscarriages: a case–control study in a South Indian population. Reprod Sci. 2008;15:817–24.

    Article  CAS  PubMed  Google Scholar 

  47. Sipak-Szmigiel O, Cybulski C, Lubiński J, Ronin-Walknowska E. HLA-G polymorphism in a Polish population and reproductive failure. Tissue Antigens. 2008;71:67–71.

    CAS  PubMed  Google Scholar 

  48. Xue S, Yang J, Yao F, Xu L, Fan L. Recurrent spontaneous abortions patients have more −14 bp/+14 bp heterozygotes in the 3′UT region of the HLA-G gene in a Chinese Han population. Tissue Antigens. 2007;69:153–5.

    Article  CAS  PubMed  Google Scholar 

  49. Tripathi P, Abbas A, Naik S, Agrawal S. Role of 14-bp deletion in the HLA-G gene in the maintenance of pregnancy. Tissue Antigens. 2004;64:706–10.

    Article  CAS  PubMed  Google Scholar 

  50. Shao JC, Hu DC, Chen J, Liu YD, Wang ZM. Relationship of polymorphism of HLA-G 14 bp and the expression of HLA-G mRNA with unexplained recurrent spontaneous abortion. J Pract Obstet Gynecol. 2011;27:698–701.

    CAS  Google Scholar 

  51. Zhao YM, ZhenG ML, Zhang GL, Zhang YL, Hua AL, He JM. Related study between Serum levels of sHLA-G, HLA-G14bp insertion/deletion polymorphism and recurrent spontaneous abortion. Shanxi Med J. 2009;38:390–1.

    CAS  Google Scholar 

  52. Cecati M, Giannubilo SR, Emanuelli M, Tranquilli AL, Saccucci F. HLA-G and pregnancy adverse outcomes. Med Hypotheses. 2011;76:782–4.

    Article  CAS  PubMed  Google Scholar 

  53. Rizzo R, Andersen AS, Lassen MR, Sorensen HC, Bergholt T, Larsen MH, et al. Soluble human leukocyte antigen-G isoforms in maternal plasma in early and late pregnancy. Am J Reprod Immunol. 2009;62:320–38.

    Article  CAS  PubMed  Google Scholar 

  54. Hill JA, Anderson DJ. Immunological mechanisms in recurrent spontaneous abortion. Arch Immunol Ther Exp. 1990;38:111–9.

    CAS  Google Scholar 

  55. Rai R, Regan L. Recurrent miscarriage. Lancet. 2006;368:601–11.

    Article  PubMed  Google Scholar 

  56. Kruse C, Steffensen R, Varming K, Christianen OB. A study of HLA-DR and -DQ alleles in 588 patients and 562 controls confirms that HLA-DRB1*03 is associated with recurrent miscarriage. Hum Reprod. 2004;19:1215–21.

    Article  CAS  PubMed  Google Scholar 

  57. Christiansen OB, Pedersen B, Rosgaard A, Husth M. (2002) A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage. Hum Reprod. 2002;17:809–16.

    Article  CAS  PubMed  Google Scholar 

  58. Adams KM, Nelson JL. Microchimerism: an investigative frontier in autoimmunity and transplantation. J Am Med Assoc. 2004;291:1127–31.

    Article  CAS  Google Scholar 

  59. Huppertz B, Kaufmann P, Kingdom J. Trophoblast turnover in health and disease. Fetal Matern Med Rev. 2002;13:103–18.

    Article  Google Scholar 

  60. Christiansen OB, Pedersen B, Nielsen HS, Nybo Andersen AM. Impact of the sex of first child on the prognosis in secondary recurrent miscarriage. Hum Reprod. 2004;19(12):2946–51.

    Article  CAS  PubMed  Google Scholar 

  61. Bulletti C, Flamigni C, Giacomucci E. Reproductive failure due to spontaneous abortion and recurrent miscarriage. Hum Reprod Update. 1996;2:118–36.

    Article  CAS  PubMed  Google Scholar 

  62. Sbracia M, Cozza G, Grasso JA, Mastrone M, Scarpellini F. Semen parameters and sperm morphology in men in unexplained recurrent spontaneous abortion, before and during a 3 year follow-up period. Hum Reprod. 1996;11:117–20.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Center of Reproductive Medicine, The West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China

    Wei Fan, Shangwei Li & Zhongying Huang

  2. Nursing Faculty of the West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China

    Qiong Chen

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  1. Wei Fan
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Correspondence to Wei Fan.

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Capsule The comprehensive meta-analysis indicated that there was insufficient evidence to demonstrate a conclusive association between the HLA-G 14-bp insertion/deletion polymorphism and the risk of RM. But HLA-G 14-bp insertion/deletion polymorphic variation was associated with RM risk in patients with three or more miscarriages.

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Fan, W., Li, S., Huang, Z. et al. Relationship between HLA-G polymorphism and susceptibility to recurrent miscarriage: A meta-analysis of non-family-based studies. J Assist Reprod Genet 31, 173–184 (2014). https://doi.org/10.1007/s10815-013-0155-2

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