The Role of HLA-G Molecule and HLA-G Gene Polymorphisms in Tumors, Viral Hepatitis, and Parasitic Diseases

Abstract

Considering that the non-classical HLA-G molecule has well-recognized tolerogenic properties, HLA-G expression is expected to be deleterious when present in tumor cells and in cells chronically infected by viruses, whereas HLA-G expression is expected to be advantageous in autoimmune disorders. The expression of HLA-G on tissue or peripheral blood cells, the levels of soluble HLA-G and polymorphic sites along the gene have been studied in several disorders. In this study, we revised the role of the molecule and polymorphic sites along the HLA-G gene in tumors, viral hepatitis, and parasitic disorders. Overall, several lines of evidence clearly show that the induction of HLA-G expression in tumors has been associated with worse disease outcome and disease spread. In addition, the few studies conducted on hepatitis and parasitic disorders indicate that HLA-G may contribute to disease pathogenesis. Few isolated polymorphic sites, primarily located at the coding or 3' untranslated HLA-G region, have been evaluated in these disorders, and a complete HLA-G typing together with the study of gene regulatory elements may further help on the understanding of the influence of the genetic background on disease susceptibility.

Keywords: HLA-G; parasitic disorders; polymorphism; tumors; viral hepatitis.

Figure 1

Variation sites at the 5′ upstream regulatory region (5′URR) of the HLA-G gene (1.4 kb upstream of ATG), as well as the target binding sites of the described transcriptional factors. The position of the variation sites is determined in relation to Adenine of the initiation codon ATG. *Since there is no official nomenclature for 5′URR haplotypes, they were designed as previously reported (10). Transcription factors: CREB1, CAMP responsive element binding protein 1; ATF1, cyclic AMP-dependent transcription factor ATF-1; RREB1, Ras responsive element binding protein 1; IRF1, interferon regulatory factor 1; p50, nuclear factor NF-κ-B p105 subunit; RFX5, DNA-binding protein RFX5 (RFX family); PR, progesterone receptor. I, insertion of a guanine at position −540; Δ, deletion of an adenine at position −533.

Figure 2

Variation sites at the 3′ untranslated region (3′UTR) of the HLA-G gene that may influence HLA-G expression. Polymorphic sites associated with diseases presented in this review are underlined. Arrows indicate polymorphic sites that have been functionally studied. *Since there is no official nomenclature for 3′UTR haplotypes, they were designed as previously reported (11). DEL, deletion; INS, insertion.

Figure 3

Variation sites at the coding region of the HLA-G gene from exon 1–4. Polymorphic sites associated with diseases presented in this review are underlined. *Haplotypes presenting a global frequency higher than 1% in worldwide populations. Amino acids: A, alanine; S, serine; F, phenylalanine; Y, tyrosine; T, threonine; M, methionine; Q, glutamine; R, arginine; E, glutamic acid; P, proline; H, histidine; G, glycine; D, aspartic acid; V, valine; C, cysteine; L, leucine; I, isoleucine; W, tryptophan. Δ, deletion.