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.

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The AluyHG element belongs to the AluYb8 subfamily. It is a polymorphic insertion, located approximately 20 kb from the HLA-G 3'-untranslated region (3'-UTR), which has been used for evolution studies because it exhibits identity for descendants and it is still polymorphic in the human genome. To understand the evolutionary mechanisms acting on HLA-G, we evaluated the presence or absence of the AluyHG element, associating this variable site with others observed at HLA-G coding, 3'-UTR, or both regions in four distinct populations (Brazilian, French, Congolese, and Senegalese). The results were compared with the 1000Genomes Consortium data. The worldwide AluyHG frequencies showed an increment, starting lower in Africa and increasing following distance and time of human dispersion out of Africa. The same haplotype pattern was observed in all populations, indicating that most of the HLA-G haplotypes already detected were originated earlier in Africa, before Homo sapiens dispersion. The AluyHG insertion was associated with the G*01:01:01:01/UTR-1 haplotype, with rare recombinants. Despite its high frequency in worldwide populations, the G*01:01:01:01/UTR-1 haplotype should be very recent. The low frequency of recombinants indicates that the rate of recombination at the HLA-G gene is very low.

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MicroRNAs (miRNAs) play a critical role on biological and cellular processes; the search for functional markers may be of importance for differential diagnosis, prognosis, and development of new therapeutic regimens. In this context, we evaluated the bone marrow miRNA profile of Brazilian children exhibiting T‐ or B‐cell acute lymphoblastic leukemia (T‐ALL or B‐ALL), using massive parallel sequencing, using the HiSeq 2500 platform (Illumina). The differential expression analysis was conducted considering a leave‐one‐out approach and FDR ≤ 0.05. Machine learning algorithms were applied to search for the disease subset biomarkers. Target prediction, functional enrichment, and classification of biological categories were also performed. Sixteen miRNAs were differentially expressed between T‐ and B‐ALL, of which 10 (miR‐708‐5p, miR‐497‐5p, miR‐151a‐5p, miR‐151b, miR‐371b‐5p, miR‐455‐5p, miR‐195‐5p, miR‐1266‐5p, miR‐574‐5p, and miR‐425‐5p) were downregulated and six (miR‐450b‐5p, miR‐450a‐5p, miR‐542‐5p, miR‐424‐5p, miR‐629‐5p, and miR‐29c‐5p) were upregulated in childhood T‐ALL. These miRNAs may be used for distinguishing childhood lymphoblastic leukemia subtypes, since it provided the clear separation of patients in these two distinct groups. Six relevant biological pathways were identified according to their role in leukemia, namely, viral carcinogenesis, cell cycle, and B‐cell receptor signaling pathways for induced miRNAs and TGF‐beta signaling, apoptosis, and NF‐kappa B signaling for the repressed miRNAs, of which several miRNA gene targets participate in cell differentiation and hematopoiesis processes. Machine learning analysis pointed out miR‐29c‐5p expression as the best discriminator between childhood T‐ and B‐ALL, which is involved in calcium signaling, critical for B‐cell lymphocyte fate. Further studies are needed to assure the role of the 16 miRNAs and miR‐29c‐5p on acute lymphoblastic leukemia subtypes and on disease prognosis.

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