The 3'-untranslated region of the HLA-G gene in relation to pre-eclampsia: revisited.

Abnormal human leukocyte antigen G (HLA-G) expression may be involved in pre-eclampsia. A 14 bp insertion/deletion polymorphism exists in exon 8 of the HLA-G gene. Fetal +14/+14 bp HLA-G genotype may predispose to pre-eclampsia in the mother. Other polymorphisms, besides the 14 bp polymorphism (rs66554220), in the 3'-untranslated region (3'-UTR) (exon 8) of the HLA-G gene might be associated with severe pre-eclampsia, especially in primiparas. By haplotype-specific polymerase chain reaction amplification and DNA sequence analysis in the offspring from 50 pre-eclamptic cases and 85 controls (35 and 58 primiparas), 4 single nucleotide polymorphisms (SNPs) were detected in exon 8 of the HLA-G gene [SNP2995 (rs1710), SNP3127 (rs1063320), SNP3172 (rs9380142), and SNP3181 (rs1610696)]. Complete linkage disequilibrium between the +14 bp allele and three of the SNPs (SNP2995, SNP3127, and SNP3172) were observed. Two of the polymorphisms (SNP3172 and SNP3181) were located right before and after an AUUUA-pentamer sequence; AU-rich sequences seem to be involved in mRNA stability. However, only the genotypes of the earlier showed 14 bp polymorphism and the SNP3127 (with a C to G substitution; P = 0.008, P(C) = 0.04) were significantly associated with severe pre-eclampsia in primiparas. In conclusion, this study indicates that the +14 bp HLA-G allele defines a nearly unique exon 8 haplotype, and fetuses homozygous for this haplotype [SNP 2995(C)/SNP 3127(G)/SNP 3172(A)/SNP 3181(G)/+14 bp] are associated with severe pre-eclampsia in primiparas.

Association between human leukocyte antigen-G genotype and success of in vitro fertilization and pregnancy outcome.

To determine if a 14-bp deletion/insertion polymorphism in the 3'-untranslated region of exon 8 of the gene encoding human leukocyte antigen (HLA)-G in a homozygous form is associated with repeated, unsuccessful in vitro fertilization (IVF) treatments, and with increased risk of recurrent spontaneous abortions (RSA), 29 white women undergoing IVF treatments, 61 RSA women and 93 fertile controls were HLA-G genotype. The HLA-G genotype, homozygous for the presence of the 14 bp sequence in exon 8, was significantly associated with reduced fertility with respect to unsuccessful IVF treatments and increased risk of recurrent miscarriage (combined P < 0.01). The 14-bp insertion/deletion polymorphism is associated with differences in HLA-G mRNA alternative splicing and levels of HLA-G. This might affect a possible immunomodulatory role of HLA-G expression in both the mother and foetus during implantation and pregnancy.

HLA-G polymorphisms in couples with recurrent spontaneous abortions.

The etiology of a fraction of recurrent spontaneous abortions (RSA) may involve immunological mechanisms. Aberrant profiles of Th1 and Th2 cytokines have been observed which are not present in uncomplicated pregnancies. Studies of classical HLA class I and II antigens in relation to RSA have not been conclusive. Furthermore, these antigens are not expressed in the placenta with the exception of HLA-C. However, HLA-G is expressed on especially invasive cytotrophoblasts and exists in both membrane and soluble forms. HLA-G may be involved in materno-fetal tolerance. Therefore, 61 RSA couples (with three or more spontaneous abortions) and 47 fertile control couples were HLA-G genotyped by direct DNA sequencing and analyzed for specific polymorphisms. No statistically significant differences were observed in the distribution of HLA-G alleles between controls and RSA couples, however, 15% of the RSA women carried the HLA-G*0106 allele compared to 2% of the control women. The 14 bp deletion polymorphism in exon 8 was investigated separately. There were a greater number of heterozygotes for the 14 bp polymorphism in the group of fertile control women than expected, according to Hardy-Weinberg equilibrium. Furthermore, the HLA-G alleles without the 14 bp sequence were prominent in the RSA males in contrast to the RSA women in whom alleles including the 14 bp sequence were frequently observed, especially as homozygotes. These results are discussed in relation to two hypotheses concerning HLA-G and RSA. A hypothesis of HLA-G histo-incompatibility between fetus/placenta and the mother was not supported by the data. Another hypothesis concerned certain HLA-G alleles associated with an altered expression profile of HLA-G isoforms or reduced expression of certain HLA-G isoforms.