Research Article: Association of HLA-A and Non-Classical HLA Class I Alleles

Date Published: October 4, 2016

Publisher: Public Library of Science

Author(s): Federico Carlini, Virginia Ferreira, Stéphane Buhler, Audrey Tous, Jean-François Eliaou, Céline René, Jacques Chiaroni, Christophe Picard, Julie Di Cristofaro, Antony Nicodemus Antoniou.


The HLA-A locus is surrounded by HLA class Ib genes: HLA-E, HLA-H, HLA-G and HLA-F. HLA class Ib molecules are involved in immuno-modulation with a central role for HLA-G and HLA-E, an emerging role for HLA-F and a yet unknown function for HLA-H. Thus, the principal objective of this study was to describe the main allelic associations between HLA-A and HLA-H, -G, -F and -E. Therefore, HLA-A, -E, -G, -H and -F coding polymorphisms, as well as HLA-G UnTranslated Region haplotypes (referred to as HLA-G UTRs), were explored in 191 voluntary blood donors. Allelic frequencies, Global Linkage Disequilibrium (GLD), Linkage Disequilibrium (LD) for specific pairs of alleles and two-loci haplotype frequencies were estimated. We showed that HLA-A, HLA-H, HLA-F, HLA-G and HLA-G UTRs were all in highly significant pairwise GLD, in contrast to HLA-E. Moreover, HLA-A displayed restricted associations with HLA-G UTR and HLA-H. We also confirmed several associations that were previously found to have a negative impact on transplantation outcome. In summary, our results suggest complex functional and clinical implications of the HLA-A genetic region.

Partial Text

A complete Human Leukocyte Antigen (HLA) match is associated with better long term survival in transplant patients, however the effects of HLA-A, -B and -DRB1 matching are unequal and also depend upon the organ being transplanted. HLA-A mismatches were found to have less influence on kidney allografts than HLA-B mismatches [1]. This difference could reflect the higher number of HLA-B alleles compared to HLA-A and/or the cytotoxic T-cell allo-repertoire for HLA-A and -B antigens, as lower frequencies of Cytotoxic T-Lymphocyte precursor (CTLp) are found for HLA-A mismatches than for HLA-B mismatches [2, 3]. Few amino acid polymorphisms at functionally important positions of the antigen recognition site of the HLA-A molecule have been shown to have a significant influence on clinical outcome [4]. In liver transplant patients however, only HLA-A mismatching was associated to a negative effect on patient survival and a higher recurrence of the hepatitis C virus, whereas no HLA-B and -DR mismatches had no effect [5]. In Lung Transplantation (LTx), the risk of Bronchiolitis Obliterans Syndrome only increased in the presence of two HLA-A mismatches, not for 0 or 1 mismatch or for HLA-B or -DR mismatches [6]. These data support the hypothesis that HLA-A mismatching leads to a particular immunological situation in organ transplantation compared to other loci. The HLA-A molecule displays specific features compared to HLA-B that could account for its particular role: HLA-A and HLA-B alleles carry an unpaired cysteine at different positions of the cytoplasmic tail domain (respectively at positions 339 and 325), which is reported to be involved in recycling, targeting for degradation and influencing recognition by NK receptors as well as in the formation of fully folded MHC class I dimers in exosomes [7]. Other genes, in association/linkage disequilibrium with HLA-A, could also induce either alloreactivity or tolerance. Indeed, the HLA-A locus on chromosome 6 is surrounded by HLA class Ib (non-classical) genes: HLA-E (at the centromeric end), HLA-G, -H and HLA-F (at the telomeric end).

This study was devoted to the analysis of allelic associations between the HLA class Ia locus HLA-A, and the HLA class Ib loci HLA-E, -H, -G, HLA-G UTRs and -F which are all physically located within a region of 724 kb on chromosome 6. HLA-A seems to be involved in transplantation outcome in a different way from HLA-B or HLA-DRB1 [1, 3]. This singular feature could be due to the HLA-A molecule per se and/or be a consequence of yet unknown patterns of linkage disequilibrium between HLA-A and nearby class Ib genes.