Variation in the HLA-G Promoter Region Influences Miscarriage Rates

• Published in: American journal of human genetics Vol. 72; no. 6; pp. 1425 - 1435
• Main Authors: Ober, Carole, Aldrich, Carrie L., Chervoneva, Inna, Billstrand, Christine, Rahimov, Fedik, Gray, Heather L., Hyslop, Terry
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01-06-2003; University of Chicago Press; The American Society of Human Genetics
• Subjects: Abortion, Spontaneous - genetics; Alleles; Biological and medical sciences; Diseases of mother, fetus and pregnancy; Female; Gene Frequency; Genetic Variation; Genotype; Gynecology. Andrology. Obstetrics; Haplotypes; Histocompatibility Antigens Class I - genetics; HLA Antigens - genetics; HLA-G Antigens; Humans; Medical sciences; Mutation; Polymorphism, Single Nucleotide; Pregnancy; Pregnancy. Fetus. Placenta; Promoter Regions, Genetic; Risk Factors; Human; HLA-System; Pregnancy disorders; Major histocompatibility system; Rate; Variations; Abortion; Promoter; Pathogenic; Cytogenetics; Female; Region; Molecular biology
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/375501

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.