A tug-of-war between tolerance and rejection - New evidence for 3′UTR HLA-G haplotypes influence in recurrent pregnancy loss

HLA-G is a molecule essential to the maintenance of the maternal-fetal interface tolerance, thus contributing to a healthy pregnancy. Here we investigate the role of HLA-G single nucleotide polymorphisms (SNPs) and whether a specific HLA-G haplotype influence or not recurrent pregnancy loss (RPL) risk. A total of 296 DNA samples from RPL (N = 140) and controls (N = 156) were evaluated. The HLA-G 3′UTR region was sequenced and eight major SNPs were evaluated (14pb insertion/deletion, +3003T/C, +3010C/G, +3027C/A, +3035C/T, +3142G/C, +3187A/G, +3196C/G). A high linkage disequilibrium (LD) among all pairs and a perfect LD between +3010C/G and +3142G/A (D′ = 1.0, r2 = 1.0) were observed. Our data showed an increased risk to +3010CC genotype carriers in comparison with control [odds ratio (OR) 2.05 95% confidence interval (CI) 1.05-4.00, p = 0.035] and to a decreased risk of RPL in +3142CC genotype carriers (OR = 0.49 95%CI 0.25-0.95, p = 0.035) and +3187AG genotype carriers (OR = 0.58 95%CI 0.35-0.94, p = 0.029). A total of eight haplotypes were observed in the sample, being UTR-1 and UTR-2 the most represented. An association between UTR-1 haplotype carriers with a reduced risk of both RPL and secondary RPL was observed. Our results indicate that the HLA-G 3′UTR plays important roles in RPL and might be an important marker of susceptibility to this, and possible to other, pregnancy disorders.