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Hum. Reprod. Advance Access published online on October 27, 2005
Human Reproduction, doi:10.1093/humrep/dei366
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© The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received June 6, 2005
Revised September 14, 2005
Accepted September 20, 2005

Article

Maternal CD46H*2 and IL1B-511*1 homozygosity in T helper 1-type immunity to trophoblast antigens in recurrent pregnancy loss

Zhigang C. Wang 1*, Joseph A. Hill 2, Edmond J. Yunis 3, Ling Xiao 1, and Deborah J. Anderson 1

1 Fearing Laboratory, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
2 Fearing Laboratory, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; The Fertility Center of New England, Reading, MA 01867, USA
3 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA

* To whom correspondence should be addressed.
Zhigang C. Wang, E-mail: zhigang_wang{at}dfci.harvard.edu


  Abstract

BACKGROUND: Women with recurrent pregnancy loss (RPL) and T-helper (Th)1-type immunity to trophoblast antigens have an increased frequency of the IL1B-511*1 promoter variant. Since CD46 gene products also regulate maternal immune responses including Th1 immunity, we investigated whether CD46 gene polymorphisms are also associated with RPL in women with and without Th1 immunity to trophoblast, and the possibility of a synergistic effect with the IL1B-511*1 promoter variant. METHODS: A case-controlled study was performed to document HindIII site polymorphism in intron 1 of the CD46 gene in 131 women with RPL and 72 fertile controls. Clinical information, Th1-type immune responsiveness to trophoblast in women with RPL history, and IL1B promoter allelotypes for this cohort were documented in a previous study. RESULTS: The frequency of the CD46H*2 allele and CD46H*2 homozygosity were significantly increased in women with RPL compared with fertile controls (P<0.028 and P<0.011). CD46H*2 homozygosity was highly associated with RPL-Th1(+) (32.4 versus 9.7% in fertile controls, P<0.0045). Logistic regression analysis revealed that women homozygous for both the IL1B-511*1 and CD46H*2 alleles had an extremely high risk of RPL-Th1(+) [exponential coefficients (EC) = 24]. Among women with RPL, homozygosity at both alleles, but not each alone, significantly increased the risk of Th1 immunity to trophoblast antigens (EC = 16), suggesting a possible genetic interaction between these two alleles in the development of Th1 immunity. CONCLUSIONS: The combination of homozygosity for both IL1B-511*1 and CD46H*2 alleles is a high risk factor for RPL-Th1(+).

Keywords: CD46/IL1B/Th1 immunity/recurrent pregnancy loss.
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