Skip to main content
SpringerLink
Log in

Association Between Novel HLA-G Genotypes and Risk of Recurrent Miscarriages: A Case-Control Study in a South Indian Population

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

HLA-G is a nonclassical histocompatibility complex member associated with fetal tolerance of the mother observed during pregnancy. Despite its being a less polymorphic gene, a number of studies have evaluated the role of HLA-G gene polymorphisms on the risk of pregnancy-related complications. A 14-bp deletion polymorphism in exon 8 (3′UTR) was known to influence the levels of soluble HLA-G, differential splicing of the transcript, and also the induction of interleukin-10 secretion. The present study is aimed at evaluating the variations in exon 2 and exon 8 of the HLA-G gene for the risk of recurrent miscarriages in South Indian women. A total of 169 cases and 92 controls are included in the study. Six novel polymorphisms were identified, 2 of which are in intron 2 near the exon-intron junction and 4 of which are present downstream to the 14-bp deletion in 3′UTR. The exon 2 and intron polymorphisms failed to show any association. The T1570C and C1594A polymorphisms showed a significant association (P = .002 and .021) with the risk of miscarriage after categorization based on the 14-bp deletion. Linkage disequilibrium analysis showed that the T allele of T1570C is in linkage disequilibrium with the 14-bp deletion in cases but not in controls. In silico RNA folding studies indicate that the T allele forms a more stable secondary structure than the C allele, giving rise to a more stable transcript. The authors demonstrate a significant relation between the two 3′UTR polymorphisms and recurrent miscarriages.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Christiansen OB, Nielsen HS, Kolte AM. Inflammation and miscarriage. Semin Fetal Neonatal Med. 2006;11(5):302–308.

    Article  Google Scholar 

  2. Lachapelle MH, Miron P., Hemmings R., Roy DC, Endometrial T, B, and NK cells in patients with recurrent spontaneous abortion: altered profile and pregnancy outcome. J Immunol. 1996;156:4027–4034.

    CAS  PubMed  Google Scholar 

  3. Jenkins C., Roberts J., Wilson R., MacLean MA, Shilito J., Walker JJ Evidence of a T(H)1 type response associated with recurrent miscarriage. Fertil Steril. 2000;73(6):1206–1208.

    Article  CAS  Google Scholar 

  4. 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.

    Article  CAS  Google Scholar 

  5. LeMaoult J., Le Discorde M., Rouas-Freiss N., et al. Biology and functions of human leukocyte antigen-G in health and sickness. Tissue Antigens. 2003;62:273–284.

    Article  CAS  Google Scholar 

  6. Le Gal FA, Riteau B., Sedlik C., et al. HLA-G-mediated inhibition of antigen-specific cytotoxic T lymphocytes. Int Immunol. 1999;11:1351.

    Article  Google Scholar 

  7. LeMaoult J., Krawice-Radanne I., Dausset J., Carosella ED HLA-G1-expressing antigen-presenting cells induce immunosuppressive CD4+ T cells. Proc Natl Acad Sci U S A. 2004; 101:7064.

    Article  CAS  Google Scholar 

  8. Fournel S., Aguerre-Girr M., Huc X., et al. Soluble HLA-G1 triggers CD95/CD95 ligand- mediated apoptosis in activated CD8+ cells by interacting with CD8. J Immunol. 2000;164: 6100–6104.

    Article  CAS  Google Scholar 

  9. Yie SM, Li LH, Li YM, Librach C. HLA-G protein concentrations in maternal serum and placental tissue are decreased in preeclampsia. Am J Obstet Gynecol. 2004;191:525–529.

    Article  CAS  Google Scholar 

  10. Athanassakis I., Paflis M., Ranella A., Vassiliadis S. Detection of soluble HLA-G levels in maternal serum can be predictive for a successful pregnancy. Transplant Proc. 1999;31(4):1834–1837.

    Article  CAS  Google Scholar 

  11. Steinborn A., Rebmann V., Scharf A., Sohn C., Grosse-Wilde H. Placental abruption is associated with decreased maternal plasma levels of soluble HLA-G. J Clin Immunol. 2003;23:307–314.

    Article  CAS  Google Scholar 

  12. Tripathi P., Agrawal S. Non-classical HLA-G antigen and its role in cancer progression. Cancer Invest. 2006;24(2):178–186.

    Article  CAS  Google Scholar 

  13. Nicolae D., Cox NJ, Lester LA, et al. Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Am J Hum Genet. 2005; 76(2):349–357.

    Article  CAS  Google Scholar 

  14. Cosman D., Fanger N., Borges L., et al. A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Immunity. 1997;7:273–282.

    Article  CAS  Google Scholar 

  15. Hill JA III, Choi BC Immunodystrophism evidence for a novel alloimmune hypothesis for recurrent pregnancy loss involving Th1- type immunity to trophoblast. Semin Reprod Med. 2000;18:401–405.

    Article  Google Scholar 

  16. Yie S.-M., Xiao R., Librach CL Progesterone regulates HLA-G gene expression through a novel progesterone response element. Hum Reprod Advance Access published 2006;21(10):2538–2544.

    Article  CAS  Google Scholar 

  17. Hviid TV, Hylenius S., Rørbye 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(2):63–79.

    Article  CAS  Google Scholar 

  18. Rizzo R., Hviid TV, Stignani M., et al.The HLA-G genotype is associated with IL-10 levels in activated PBMCs. Immunogenetics. 2005;57(3–4):172–181.

    Article  CAS  Google Scholar 

  19. 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(11):1005–1010.

    Article  CAS  Google Scholar 

  20. 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(1):66–69.

    Article  CAS  Google Scholar 

  21. 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;66:688–699.

    Article  CAS  Google Scholar 

  22. Kruse C., Steffensen R., Varming K., Christiansen OB A study of HLA-DR and -DQ alleles in 588 patients and 562 controls confirms that HLA-DRB103 is associated with recurrent miscarriage. Hum Reprod. 2004;19(5):1215–1221.

    Article  CAS  Google Scholar 

  23. Miller SA, Dykes DD, Polesky HF, A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16(3):1215.

    Article  CAS  Google Scholar 

  24. Excoffier L., Laval G., Schneider S. Arlequin ver. 3.0: an integrated software package for population genetics data analysis. Evolutionary Bioinformatics Online. 2005;1:47–50.

    CAS  Google Scholar 

  25. Mathews DH MEBDHT: RNAStructure, Version 3.5. Carlsbad, CA: Isis Pharmaceuticals, Inc; 1999.

    Google Scholar 

  26. Lalouel J., Rohswasser A. Power and replication in case-control studies. Am J Hypertens. 2002;15:201–205.

    Article  Google Scholar 

  27. Yie S.-M., Taylor RN, Librach C. Low plasma HLA-G protein concentrations in early gestation indicate the development of preeclampsia later in pregnancy. Am J Obstet Gynecol. 2005; 193:204–208.

    Article  CAS  Google Scholar 

  28. Rebmann V., Pfeiffer M., Ferrone S., Weiss E., Grosse-Wilde H. Detection of soluble HLA-G molecules in plasma and amniotic fluids. Tissue Antigens. 1999;53:14–19.

    Article  CAS  Google Scholar 

  29. Vauvert T., Hviid R., Rizzo R., et al. HLA-G and IL-10 in serum in relation to HLA-G genotype and polymorphisms. Immunogenetics. 2004;56:135–141.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, Andhra Pradesh, 500 007, India

    Venkata Suryanarayana MSc, Lakshmi Rao MSc, Murthy Kanakavalli MSc, Venkata Padmalatha MSc & Lalji Singh DSc

  2. Infertility Institute and Research Centre, Secunderabad, Andhra Pradesh, India

    Mamata Deenadayal MD

Authors
  1. Venkata Suryanarayana MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lakshmi Rao MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Murthy Kanakavalli MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Venkata Padmalatha MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Turalpati Raseswari MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mamata Deenadayal MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lalji Singh DSc
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lalji Singh DSc.

Additional information

We thank Ms Jayanthi for her help in patient recruitment and Mr Arvind for the computational data analysis. We acknowledge Mr Nagesh, Dr Manjula, Mr Anilkumar, and Mr Pavan for their assistance during the DNA-sequencing experiments. We are grateful to the Council of Scientific and Industrial Research, New Delhi, India, for the financial assistance supporting the study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Suryanarayana, V., Rao, L., Kanakavalli, 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. 15, 817–824 (2008). https://doi.org/10.1177/1933719107314061

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719107314061

Key words

Search

Navigation