Comprehensive analysis of HLA-G: implications for recurrent spontaneous abortion.
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.
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Dara S
DS
Berger
W Allen
WA
Hogge
M Michael
MM
Barmada
Robert E
RE
Ferrell
D000022:Abortion, Spontaneous / Q000235:genetics*; D000328:Adult; D005091:Exons / Q000235:genetics / Q000276:immunology; D005260:Female; D006680:HLA Antigens / Q000235:genetics*; D059951:HLA-G Antigens; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation; D015810:Linkage Disequilibrium; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D055815:Young Adult
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I