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

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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.

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Authors and Affiliations

  1. Departments of Human Genetics, University of Pittsburgh, A300 Crabtree Hall, Pittsburgh, Pennsylvania, 15261, USA

    Dara S. Berger PhD, M. Michael Barmada PhD & Robert E. Ferrell PhD

  2. Departments of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    W. Allen Hogge MD

Authors
  1. Dara S. Berger PhD
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  2. W. Allen Hogge MD
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  3. M. Michael Barmada PhD
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  4. Robert E. Ferrell PhD
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Correspondence to Robert E. Ferrell PhD.

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Berger, D.S., Hogge, W.A., Barmada, M.M. et al. Comprehensive Analysis of HLA-G: Implications for Recurrent Spontaneous Abortion. Reprod. Sci. 17, 331–338 (2010). https://doi.org/10.1177/1933719109356802

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