Variation in the HLA-G promoter region influences miscarriage rates.
The HLA-G gene is primarily expressed in placental cells that invade the maternal decidua during pregnancy. This gene encodes multiple isoforms that fulfill a variety of functions at the maternal-fetal interface throughout gestation. Recently, a null allele for the most abundant HLA-G isoform was associated with recurrent miscarriage in two independent studies, suggesting that reduced levels of the HLA-G1 protein may compromise successful pregnancy. We initiated the present study to determine whether other polymorphisms that could affect expression levels of HLA-G were associated with fetal loss in women participating in a 15-year prospective study of pregnancy outcome. We genotyped these subjects for 18 single-nucleotide polymorphisms in the 1,300 bp upstream of exon 1, 13 of which were identified as part of this study, as well as for an insertion/deletion (in/del) polymorphism in the 3' untranslated region. The 18 SNPs defined eight unique haplotypes. One polymorphism, -725C/G, was associated with fetal loss, with an increased risk for miscarriage in couples in which both partners carried the -725G allele, compared with couples not carrying this allele (odds ratio 2.76, 95% confidence interval 1.08-7.09; P=.035). Further, the G at nucleotide -725 creates a CpG dinucleotide, and we demonstrate that this CpG site is methylated on -725G alleles. Overall, this study identified extraordinary levels of variation in the 5'-upstream regulatory region of HLA-G and provides evidence for an association between a promoter-region SNP and fetal loss rates, further attesting to the novel features and critical role of this gene in pregnancy.
Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA. c-ober@genetics.uchicago.edu
Carole
C
Ober
Carrie L
CL
Aldrich
Inna
I
Chervoneva
Christine
C
Billstrand
Fedik
F
Rahimov
Heather L
HL
Gray
Terry
T
Hyslop
D000022:Abortion, Spontaneous / Q000235:genetics*; D000483:Alleles; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D059951:HLA-G Antigens; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012307:Risk Factors
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I