A Comprehensive Study of Polymorphic Sites along the HLA-G Gene: Implication for Gene Regulation and Evolution

Abstract

HLA-G molecule plays an important role on immune response regulation and has been implicated on the inhibition of T and natural killer cell cytolytic function and inhibition of allogeneic T-cell proliferation. Due to its immune-modulator properties, the HLA-G gene expression has been associated with the outcome of allograft and of autoimmune, infectious, and malignant disorders. Several lines of evidence indicate that HLA-G polymorphisms at the 5'-upstream regulatory region (5' URR) and 3'-untranslated region (3' UTR) may influence the HLA-G expression levels. Because Brazilians represent one of the most heterogeneous populations in the world with the widest HLA-G coding region variability already detected among the studied populations, a high level of variability and haplotype diversity would be expected in Brazilians. On this basis, the 5' URR, coding, and 3' UTR variability were evaluated in a Brazilian series consisting of 100 healthy bone marrow donors, as well as the linkage disequilibrium pattern along the gene and the extended haplotypes encompassing several gene segment variations. The HLA-G locus seems to present six different HLA-G lineages showing functional variations mainly in nucleotides of the regulatory regions. Differences were observed at the 5' URR in positions that either coincide with or are close to transcription factor-binding sites and at the 3' UTR mainly in positions that have already been reported to influence HLA-G mRNA availability. We report several lines of evidence for balancing selection acting on the regulatory regions, which may indicate that these HLA-G lineages may be related to the differential HLA-G expression profiles.

HLA-G regulatory haplotypes and implantation outcome in couples who underwent assisted reproduction treatment

“…We also estimated the most frequently haplotypes in the 5 0 URR plus SNP À964A/G and 14-bp ins/del in the 3 0 UTR of the HLA G gene (cut-off = 0.01) for both the case and control groups showed in Table 2, based on results from Castelli et al 2011 [28]. Five haplotypes were observed exclusively in the control group, and 9 haplotypes were shared by both groups.…”

“…In summary, the analysis of the promoter region SNPs in the HLA-G gene (Haplotype Castelli et al, 2011 [28] plus À964A/G) plus the 14-bp ins/del polymorphism and its role on infertility showed that the Haplotype 2 was related to a susceptibility effect (couples that underwent ART), when compared to Haplotype 3, Haplotype 5, Haplotype 8 and Haplotype 11 with trend, (protective effect, successful pregnancy). It deserves to be mentioned that the SNP À1140A/T, located in the LCR/TSRE regulatory region, may have an important role on HLA-G gene expression, since it is considered an enhancer site that is recognized by transcriptional factors [35].…”

HLA-G expression levels influence the tolerogenic activity of human DC-10

“…We observed that the 14bp Ins allele was significantly highly represented both in a single dose (66%) and in double copy (45%) in donors with HLA-G low DC-10 compared to those with HLA-G high DC-10 (36%, P=0.0009 and 14%, P=0.0065, respectively; Figure 6A). Since 14bp Ins is in strong linkage disequilibrium with G in position +3142, 32 we classified donors according to the presence of the 14bp Ins/Del and +3142 C/G polymorphisms as follows: InsG/InsG, DelC/DelC, DelC/InsG, and DelG/X. The relative frequencies of these alleles and genotypes are shown in Figure 6B.…”

Human leukocyte antigen–G 3′ untranslated region polymorphisms are associated with better kidney allograft acceptance

“…Variability at HLA-G 3=UTR may also modulate HLA-G isoform expression, as differential alternative splicing may be observed according to the HLA-G allele [24]. In addition, considering that HLA-G 3= UTR polymorphic sites are in linkage disequilibrium with those at coding and promoter regions [40], both transcriptional and post-transcriptional influences may account for the final HLA-G expression, which in concert may contribute to susceptibility to or protection against allograft rejection.…”