Abstract
The HLA-G molecule plays an important role in immunomodulation. In a previous study carried out on a southern French population our team showed that HLA-G haplotypes, defined by SNPs in the coding region and specific SNPs located in 5′URR and 3′UTR regulatory regions, are associated with differential soluble HLA-G expression (sHLA-G). Furthermore, the structure of these HLA-G haplotypes appears to be conserved in geographically distant populations.The aim of our study is to confirm these expectations in a sub-Saharan African population and to explore additional factors, such as HLA-A alleles, that might influence sHLA-G expression.DNA and plasma samples were collected from 229 Malians; HLA-G and HLA-A genotyping were respectively performed by the Snap Shot® method and by Luminex™ technology. sHLA-G dosage was performed using an ELISA kit. HLA-G and HLA-A allelic and haplotypic frequencies were estimated using an EM algorithm from the Gene[Rate] program. Associations between genetic and non genetic parameters with sHLA-G were performed using a non-parametric test with GRAPH PAD Prism 5.Our results reveal a good conservation of the HLA-G UTR haplotype structure in populations with different origins and demographic histories. These UTR haplotypes appear to be involved in different sHLA-G expression patterns. Specifically, the UTR-2 haplotype was associated with low sHLA-G levels, displaying a dominant negative effect. Furthermore, an allelic effect of both HLA-G and HLA-A, as well as non genetic parameters, such as age and gender possibly linked to osteogenesis and sexual hormones, also seem to be involved in the modulation of sHLA-G.These data suggest that further investigation in larger cohorts and in populations from various ethnical backgrounds is necessary not only to detect new functional polymorphism in HLA-G regulatory regions, but also to reveal the extent of biological phenomena that influence sHLA-G secretion and this might therefore have an impact on transplantation practice.
Highlights
The role of the non-classical class Ib Human LeukocyteAntigen-G (HLA-G) in immune-tolerance has been well documented [1,2,3]
The five Human LeukocyteAntigen-G (HLA-G) alleles previously reported in the French population (VBMD) were all observed in Malians
Malian samples displayed a significantly higher frequency (p,0.001) for HLA-G*01:04, G*01:03, G*01:05N as compared to Volunteer Bone Marrow Donors (VBMD), while HLA-G*01:01 frequency was significantly higher in VBMD than in Malians (p,0.001); no statistical difference was found for G*01:06 (Table 1)
Summary
Background The role of the non-classical class Ib Human LeukocyteAntigen-G (HLA-G) in immune-tolerance has been well documented [1,2,3]. Tolerogenic properties of HLA-G were initially identified in the cytotrophoblast and correlated with feto-maternal tolerance [4,5,6,7]. Several studies have shown a clinical correlation between expression of soluble and/or membrane-bound HLA-G and reduction of rejection risk in heart, lung, liver and kidney transplant patients or Graft versus Host disease [19,20,21,22]. Contrary to the classical HLA class I loci, HLA-G is characterized by a low polymorphism in the coding regions. To this day, 50 HLA-G alleles have been identified, which encode 16 trans-membrane proteins (HLA-G*01:01 to G*01:04, G*01:06 to G*01:12 and G*01:14 to G*01:18) and two truncated proteins (HLAG*01:05N and G*01:13N) [23]. A higher degree of polymorphism has been observed in the non-coding regions 59URR (Upstream Regulatory Region) and 39UTR (UnTranslated Region) [24]
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