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TNFA Gene Promoter Polymorphisms and Susceptibility to Recurrent Pregnancy Loss in Italian Women

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Abstract

The aim of this study was to investigate the relationship between serum tumor necrosis factor α (TNF-α) levels and single nucleotide polymorphisms (SNPs) of the TNFA gene promoter (-376G/A, -308G/A, and -238G/A) in 100 Italian Caucasian women with reproductive failure and 100 fertile controls. Molecular analysis of TNFA SNPs showed higher frequencies of -238G allele (P =.028) as well as the presence of a 3-loci haplotype (-376G/-308A/-238G; P =.020) in fertile controls compared to women with reproductive failure. Serum TNF-α levels were higher in study women compared to controls (P =.001). Of interest, the TNFA-376G/-308A/-238G haplotype was an independent predictor of low TNF-α levels (P =.021) and miscarriage (P =.023) in multivariate analyses. In conclusion, these findings support the concept of an association of TNFA polymorphisms and recurrent pregnancy loss (RPL). In particular, the TNFA-238GG variant and the TNFA -376G/-308A/-238G haplotype might represent protective factors, probably through reduced TNF-α production and/or mediated responses.

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References

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

    Article  PubMed  Google Scholar 

  2. Kwak-Kim JY, Chung-Bang HS, Ng SC, et al. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy loss and in infertile women with multiple implantation failures after IVF. Hum Reprod. 2003;18(4):767–773.

    Article  CAS  PubMed  Google Scholar 

  3. Zolti M, Ben-Rafael Z, Meirom R, et al. Cytokine involvement in oocytes and early embryos. Fertil Steril. 1991;56(2): 265–272.

    Article  CAS  PubMed  Google Scholar 

  4. Arslan E, Colakoğlu M, Celik C, et al. Serum TNF-alpha, IL-6, lupus anticoagulant and anticardiolipin antibody in women with and without a past history of recurrent miscarriage. Arch Gynecol Obstet. 2004;270(4):227–229.

    Article  CAS  PubMed  Google Scholar 

  5. Clark DA, Ding JW, Yu G, Levy GA, Gorczynski R. Fgl2 prothrombinase expression in mouse trophoblast and decidua triggers abortion but may be countered by OX-2. Mol Hum Reprod. 2001;7(2):185–194.

    Article  CAS  PubMed  Google Scholar 

  6. Knackstedt MK, Zenclussen AC, Hertwig K, et al. Th1 cytokines and the prothrombinase fgl2 in stress-triggered and inflammatory abortion. Am J Reprod Immunol. 2003;49(4): 210–220.

    Article  CAS  PubMed  Google Scholar 

  7. Clark DA, Chaouat G, Arck PC, Mittruecker HW, Levy G. Cytokine-dependent abortion in CBA x DBA/2 mice is mediated by the procoagulant fgl2 prothrombinase (correction of prothombinase). J Immunol. 1998;160(2):545–549.

    CAS  PubMed  Google Scholar 

  8. Wilson AG, Di Giovine FS, Blankemore M, Duff G. Single base polymorphism in the tumor necrosis factor alpha gene detected by NcoI restriction for the PCR product. Human Mol Genet. 1992;1(5):353.

    Article  CAS  Google Scholar 

  9. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff G. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA. 1997;94(7):3195–3199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Koss K, Satsangi J, Fanning GC, Welsh KI, Jewell D. Cytokine (TNF-alpha, LT-alpha, and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies. Genes Immunol. 2000;1(3):185–190.

    Article  CAS  Google Scholar 

  11. Knight JC, Udalova I, Hill AVS, et al. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nature Genet. 1999;22(2):145–150.

    Article  CAS  PubMed  Google Scholar 

  12. Crider KS, Whitehead N, Buus R. Genetic variation associated with preterm birth: a HuGE review. Genet Med. 2005; 7(9):593–604.

    Article  CAS  PubMed  Google Scholar 

  13. Zammiti W, Mtiraoui N, Finan RR, Almawi WY, Mahjoub T. Tumor necrosis factor alpha and lymphotoxin alpha haplotypes in idiopathic recurrent pregnancy loss. Fertil Steril. 2009; 91(5):1903–1908.

    Article  CAS  PubMed  Google Scholar 

  14. Zammiti W, Mtiraoui N, Khairi H, Gris JC, Almawi WY, Mahjoub T. Associations between tumor necrosis factor-alpha and lymphotoxin-alpha polymorphisms and idiopathic recurrent miscarriage. Reproduction. 2008;135(3):397–403.

    Article  CAS  PubMed  Google Scholar 

  15. Yu XW, Li X, Ren YH, Li X. Tumour necrosis factor-alpha receptor 1 polymorphisms and serum soluble TNFR1 in early spontaneous miscarriage. Cell Biol Int. 2007;31(11): 1396–1399.

    Article  CAS  PubMed  Google Scholar 

  16. 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):171–178.

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. Pietrowski D, Bettendorf H, Keck C, et al. Lack of association of TNFalpha gene polymorphisms and recurrent pregnancy loss in Caucasian women. J Reprod Immunol. 2004;61(1): 51–58.

    Article  CAS  PubMed  Google Scholar 

  19. Costeas PA, Koumouli A, Giantsiou-Kyriakou A, Papaloizou A, Koumas L. Th2/Th3 cytokine genotypes are associated with pregnancy loss. Hum Immunol. 2004;65(2): 135–141.

    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. Baxter N, Sumiya M, Cheng S, et al. Recurrent miscarriage and variant alleles of mannose binding lectin, tumour necrosis factor and lymphotoxin alpha genes. Clin Exp Immunol. 2001; 126(3):529–534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Babbage SJ, Arkwright PD, Vince GS, et al. Cytokine promoter gene polymorphisms and idiopathic recurrent pregnancy loss. J Reprod Immunol. 2001;51(1):21–27.

    Article  CAS  PubMed  Google Scholar 

  23. Reid JG, Simpson NA, Walker RG, et al. The carriage of pro-inflammatory cytokine gene polymorphisms in recurrent pregnancy loss. Am J Reprod Immunol. 2001;45(1):35–40.

    Article  CAS  PubMed  Google Scholar 

  24. Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost. 1995;74(4):1185–1190.

    Article  CAS  PubMed  Google Scholar 

  25. Solè X, Guinò E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006;22(15):1928–1929.

    Article  PubMed  CAS  Google Scholar 

  26. Tranquilli AR, Giannubilo SR, Dell’Uomo B, Grandone E. Adverse pregnancy outcomes are associated with multiple maternal thrombophilic factors. Eur J Obstet Gynecol Reprod Biol. 2004;117(2):144–147.

    Article  PubMed  Google Scholar 

  27. Middeldorp S. Thrompophilia and pregnancy complications: cause or association? J Thromb Haemost. 2007; 5(suppl 1): 276–282.

    Article  CAS  PubMed  Google Scholar 

  28. Guzeloglu-Kayisli O, Kayisli UA, Taylor H. The role of growth factors and cytokines during implantation: endocrine and paracrine interactions. Semin Reprod Med. 2009;27(1): 62–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hill JA, Polgar K, Anderson D. T-helper1-type immunity to trophoblast in women with recurrent spontaneous abortion. JAMA. 1995;273(24):1933–1936.

    Article  CAS  PubMed  Google Scholar 

  30. 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):2219–2226.

    Article  CAS  PubMed  Google Scholar 

  31. Zhu XY, Zhou YH, Wang MY, Jin LP, Yuan MM, Li D. Blockade of CD86 signaling facilitates a Th2 bias at the maternal-fetal interface and expands peripheral CD4CCD25C regulatory T cells to rescue abortion-prone fetuses. Biol Reprod. 2005;72(2):338–345.

    Article  CAS  PubMed  Google Scholar 

  32. Raghupathy R. Th1-type immunity is incompatible with successful pregnancy. Immunol Today. 1997;18(10):478–482.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. Louis E, Franchimont D, Piron A, et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-α production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol. 1998;113(3):401–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Knight JC, Udalova I, Hill AVS, et al. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nature Genet. 1999;22(2): 145–150.

    Article  CAS  PubMed  Google Scholar 

  36. Guadagni F, Ferroni P, Basili S, et al. Correlation between tumor necrosis factor-alpha and D-dimer levels in non-small cell lung cancer patients. Lung Cancer. 2004;44(3):303–310.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Patrizia Ferroni MD, PhD.

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Palmirotta, R., La Farina, F., Ferroni, P. et al. TNFA Gene Promoter Polymorphisms and Susceptibility to Recurrent Pregnancy Loss in Italian Women. Reprod. Sci. 17, 659–666 (2010). https://doi.org/10.1177/1933719110366603

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