Program of Basic and Applied Immunology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil ; Commissariat à l'energie atomique et aux energies alternatives, institut des maladies emergentes et des therapies innovantes, service de recherches en hemato-immunologie, Hôpital Saint-Louis, Paris, France ; Universite Paris-Diderot, sorbonne paris-cite, umr-e5, institut universitaire d'hematologie, Hopital Saint-Louis, Paris, France.
PLoS One. 2013 Oct 25;8(10):e71742. doi: 10.1371/journal.pone.0071742. eCollection 2013.
HLA-G molecule has well-recognized tolerogenic properties, and the encoding gene shows lower frequency of polymorphism at the coding region but higher variability at regulatory 5' and 3' untranslated (3'UTR) regions. At least three 3'UTR polymorphic sites have been associated with HLA-G mRNA regulation, including the 14 base pair (14bp) Insertion/Deletion, +3142C-G and +3187A-G. We studied the association of polymorphic sites at 3'UTR (sequencing analysis, encompassing the 14bp Ins-Del/+3003T-C/+3010C-G/+3027C-A/+3035C-T/+3142C-G/+3187A-G/+3196C-G polymorphic sites) with plasma soluble HLA-G levels (sHLA-G, detected by ELISA) in 187 French and 153 Brazilian healthy individuals. Allele and genotype frequencies were closely similar in both populations; however, Brazilians showed a higher HLA-G 3'UTR haplotype diversity. Considering sHLA-G levels in both populations altogether, individuals presenting 14bp Del/Del showed higher levels compared to 14bpIns/Ins genotype (P <0.05); those presenting +3010C/G showed higher levels compared to the +3010C-C genotype (P< 0.05); those presenting +3027C-C showed higher levels than the +3027A-A genotype (P< 0.05); and those bearing +3035C-C showed higher levels compared to the +3035C-T (P < 0.01) and +3035T-T (P < 0.05) genotypes. The analyses of 3'UTR haplotypes showed that UTR-1 (DelTGCCCGC) was associated with higher expression of sHLA-G, whereas UTR-5 (InsTCCTGAC) and UTR-7 (InsTCATGAC) with lower expression and other UTRs (UTR-2/3/4/6) exhibited intermediate levels. Since the differential expression of HLA-G may be beneficial or harmful depending on the underlying condition, the identification of individuals genetically programmed to differentially express HLA-G may help on defining novel strategies to control the immune response against the underlying disorder.
HLA-G 分子具有公认的免疫耐受特性，其编码基因在编码区的多态性频率较低，但在调节 5'和 3'非翻译区（3'UTR）的变异性较高。至少有三个 3'UTR 多态性位点与 HLA-G mRNA 调节有关，包括 14 个碱基对（14bp）插入/缺失、+3142C-G 和+3187A-G。我们研究了 3'UTR 多态性位点（测序分析，包括 14bpIns-Del/+3003T-C/+3010C-G/+3027C-A/+3035C-T/+3142C-G/+3187A-G/+3196C-G 多态性位点）与 187 名法国和 153 名巴西健康个体血浆可溶性 HLA-G 水平（ELISA 检测的 sHLA-G）之间的关联。两种人群的等位基因和基因型频率非常相似；然而，巴西人表现出更高的 HLA-G 3'UTR 单倍型多样性。考虑到两种人群的 sHLA-G 水平，具有 14bp Del/Del 的个体与 14bpIns/Ins 基因型相比表现出更高的水平（P<0.05）；具有+3010C/G 的个体与+3010C-C 基因型相比表现出更高的水平（P<0.05）；具有+3027C-C 的个体与+3027A-A 基因型相比表现出更高的水平（P<0.05）；而具有+3035C-C 的个体与+3035C-T（P<0.01）和+3035T-T（P<0.05）基因型相比表现出更高的水平。3'UTR 单倍型分析表明，UTR-1（DelTGCCCGC）与 sHLA-G 的高表达相关，而 UTR-5（InsTCCTGAC）和 UTR-7（InsTCATGAC）与低表达相关，其他 UTRs（UTR-2/3/4/6）表现出中等水平。由于 HLA-G 的差异表达可能取决于潜在疾病的有益或有害，因此鉴定具有遗传编程差异表达 HLA-G 的个体可能有助于确定控制针对潜在疾病的免疫反应的新策略。
