Sage Journals: Discover world-class research

Abstract

Miscarriage is one of the most common pregnancy complications. Recurrent spontaneous abortion is defined as 2 or more pregnancy losses and may be associated with genetic variation. Human leukocyte antigen-G (HLA-G) is a ligand for natural killer (NK) cell receptors and has the ability to block NK cell activity, which if not blocked can potentially harm a fetus. Consequently a deletion or mutation of the HLA-G gene could lead to miscarriage. Our cases (n = 238) include Caucasian women experiencing 2 or more spontaneous abortions, and controls (n = 233) include women with at least 1 live birth and no history of SA. We sequenced approximately 1400 base pairs (bp) of the HLA-G promoter region, genotyped the 14 bp exon 8 insertion/deletion and single nucleotide polymorphism (SNP) in the coding region of HLA-G. Promoter haplotypes were constructed from sequence information. Twenty-three SNPs were observed in the promoter region with minor allele frequency >0.02. Twelve SNPs differed significantly in frequency between cases and controls. Two haplotypes incorporating these 12 SNPs accounted for 90% of haplotypes and differed significantly in frequency between the 2 populations. Cases were more likely to carry haplotype 2 (P = .0078) and controls to have haplotype 6 (P = .0004). Cases also had a higher frequency of individuals homozygous for the 14 bp insertion. Among the 12 alleles carried on haplotype 2, 5 are predicted to disrupt transcription factor binding sites. The HLA-G promoter is highly associated with the risk of spontaneous abortion, but high linkage disequilibrium in the promoter prevents assignment of the causal variant.

Keywords

Spontaneous abortion genetics HLA-G.

Get full access to this article

View all access options for this article.

References

Stephenson MD Recurrent pregnancy loss: clinical evidence for suboptimal implantation. Infert Reprod Med Clin N Amer . 2001;12(2):447-461.

Wilcox AJ , Weinberg CR , O’Connor JF , et al. Incidence of early loss of pregnancy. N Engl J Med. 1988;319(4): 189-194.

Harger JH , Archer DF , Marchese SG , Muracca-Clemens M. , Garver KL Etiology of recurrent pregnancy losses and outcome of subsequent pregnancies . Obstet Gynecol. 1983;62(5): 574-581.

Hatasaka HH Recurrent miscarriage: epidemiologic factors, definitions, and incidence. Clin Obstet Gynecol. 1994;37(3): 625-634.

Stephenson MD Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril. 1996 ;66(1):24-29.

Stray-Pedersen B. , Stray-Pedersen S. Etiologic factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion. Am J Obstet Gynecol. 1984 ;148(2): 140-146.

Christiansen OB , Nielsen HS , Kolte A. , Pedersen AT Research methodology and epidemiology of relevance in recurrent pregnancy loss. Semin Reprod Med. 2006;24(1):5-16.

Campana M. , Serra A. , Neri G. Role of chromosome aberrations in recurrent abortion: a study of 269 balanced translocations. Am J Med Genet. 1986;24(2):341-356.

Gilchrist DM , Livingston JE , Hurlburt JA , Wilson RD Recurrent spontaneous pregnancy loss. Investigation and reproductive follow-up. J Reprod Med. 1991;36(3):184-188.

10.

Lanasa MC , Hogge WA , Kubik C. , Blancato J. , Hoffman EP Highly skewed X-chromosome inactivation is associated with idiopathic recurrent spontaneous abortion. Am J Hum Genet. 1999 ;65(1):252-254.

11.

Lanasa MC , Hogge WA , Kubik CJ , et al. A novel X chromosome-linked genetic cause of recurrent spontaneous abortion. Am J Obstet Gynecol. 2001;185(3):563-568.

12.

Robinson WP , Beever C. , Brown CJ , Stephenson MD Skewed X inactivation and recurrent spontaneous abortion. Semin Reprod Med. 2001;19(2):175-181.

13.

Sangha KK , Stephenson MD , Brown CJ , Robinson WP Extremely skewed X-chromosome inactivation is increased in women with recurrent spontaneous abortion. Am J Hum Genet. 1999 ;65(3):913-917.

14.

Uehara S. , Hashiyada M. , Sato K. , Sato Y. , Fujimori K. , Okamura K. Preferential X-chromosome inactivation in women with idiopathic recurrent pregnancy loss. Fertil Steril. 2001;76:908-914.

15.

Laird SM , Tuckerman EM , Cork BA , Linjawi S. , Blakemore AI , Li TC A review of immune cells and molecules in women with recurrent miscarriage . Hum Reprod Update. 2003;9(2):163-174.

16.

Rouas-Freiss N. , Goncalves RM , Menier C. , Dausset J. , Carosella ED Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis. Proc Natl Acad Sci U S A. 1997;94(21):11520-11525.

17.

Abbas A. , Tripathi P. , Naik S. , Agrawal S. Analysis of human leukocyte antigen (HLA)-G polymorphism in normal women and in women with recurrent spontaneous abortions. Eur J Immunogenet . 2004;31(6):275-278.

18.

Aldrich CL , Stephenson MD , Karrison T. , et al. HLA-G genotypes and pregnancy outcome in couples with unexplained recurrent miscarriage. Mol Hum Reprod. 2001 ;7(12): 1167-1172.

19.

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(6):688-699.

20.

Pfeiffer KA , Fimmers R. , Engels G. , van der Ven H. , van der Ven K. The HLA-G genotype is potentially associated with idiopathic recurrent spontaneous abortion. Mol Hum Reprod . 2001;7(4):373-378.

21.

Kano T. , Mori T. , Furudono M. , 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(4):383-387.

22.

Moreau P. , Contu L. , Alba F. , et al. HLA-G gene polymorphism in human placentas: possible association of G*0106 allele with preeclampsia and miscarriage. Biol Reprod . 2008;79(3): 459-467.

23.

Sipak-Szmigiel O. , Cybulski C. , Lubinski J. , Ronin-Walknowska E. HLA-G polymorphism in a Polish population and reproductive failure. Tissue Antigens . 2008;71(1):67-71.

24.

Yan WH , Lin A. , Chen XJ , 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(6):521-523.

25.

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.

26.

Hviid TV , Hylenius S. , Hoegh AM , Kruse C. , Christiansen OB HLA-G polymorphisms in couples with recurrent spontaneous abortions. Tissue Antigens. 2002;60(2): 122-132.

27.

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(4):706-710.

28.

Ober C. , Aldrich CL , Chervoneva I. , et al. Variation in the HLA-G promoter region influences miscarriage rates. Am J Hum Genet. 2003;72(6):1425-1435.

29.

Tan Z. , Shon AM , Ober C. Evidence of balancing selection at the HLA-G promoter region. Hum Mol Genet. 2005;14(23): 3619-3628.

30.

Ober C. , Rosinsky B. , Grimsley C. , van der Ven K. , Robertson A. , Runge A. Population genetic studies of HLA-G: allele frequencies and linkage disequilibrium with HLA-A1. J Reprod Immunol. 1996;32:111-123.

31.

RDevelopmentCoreTeam. R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing; 2005.

32.

Preacher, K.J. ( 2001, April). Calculation for the chi-square test: An interactive calculation tool for chi-square tests of goodness of fit and independence [computer software]. Available from http://www.quantpsy.org .

33.

Quandt K. , Frech K. , Karas H. , Wingender E. , Werner T. MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data. Nucleic Acids Res. 1995;23(23):4878-4884.

34.

Barrett JC , Fry B. , Maller J. , Daly MJ Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005; 21(2):263-265.

35.

Scheet, P. and Stephens, M. ( 2006). A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am J Hum Genet.

Comprehensive Analysis of HLA-G: Implications for Recurrent Spontaneous Abortion

Abstract

Keywords

Get full access to this article

References