HLA-G 3′ Untranslated Region Polymorphisms Are Associated with Systemic Lupus Erythematosus in 2 Brazilian Populations

Lucena‐Silva, Norma; Souza, Veridiana Sales Barbosa de; Gomes, Rachel Novaes; Fantinatti, Alex; Muniz, Yara Costa Netto; Albuquerque, R. S. de; Monteiro, Alessandra Luna Ramos; Diniz, George Tadeu Nunes; Coêlho, Maria Rosângela Cunha Duarte; Mendes-Junior, Celso Teixeira; Castelli, Erick C.; Donadi, Eduardo Antônio

doi:10.3899/jrheum.120814

Cited by 34 publications

(40 citation statements)

References 42 publications

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“…For instance, according to our results, UTR-5 and UTR-7 frequencies are higher in recurrent pregnancy loss [50], whereas UTR-1 has been associated with reduced risk of recurrent pregnancy loss [51]. Besides, 3’UTR variants have been identified as potential prognostic biomarkers to determine susceptibility to infections [52, 53],the success of transplantation [54], and the outcome of cancer [55] and autoimmune diseases [56]. Even if we cannot neglect the influence of the HLA-G 5’URR haplotypes that are in linkage disequilibrium with 3’UTR [18], here we demonstrated that 3’UTR variants are directly involved in the differential response to cellular endogenous factors and are therefore potential target sites to consider for the design of novel therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

Haplotypes of the HLA-G 3’ Untranslated Region Respond to Endogenous Factors of HLA-G+ and HLA-G- Cell Lines Differentially

et al. 2017

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The immune checkpoint HLA-G prevents maternal rejection of the fetus and contributes in cancer invasion and acceptance of allografts. The 5’ and 3’ regulatory regions of the HLA-G gene are polymorphic and balancing selection probably maintains this variability. It is proposed that nucleotide variations may affect the level of HLA-G expression. To investigate this issue we aimed to analyze how haplotypes of the 3’ untranslated region (3’UTR) with highest worldwide frequencies, namely UTR-1, UTR-2, UTR-3, UTR-4, UTR-5, UTR-18 and UTR-7, impact the expression of a luciferase reporter gene in vitro. Experiments performed with the HLA-G positive cell lines JEG-3 (choricarcinoma) and FON (melanoma), and with the HLA-G negative cell lines M8 (melanoma) and U251MG (glioblastoma) showed that the HLA-G 3’UTR polymorphism influences the response to endogenous cellular factors and may vary according to the cell type. UTR-5 and UTR-7 impact the activity of luciferase the most whereas UTR-2, UTR-3, UTR-4, and UTR-18 have intermediate impact, and UTR-1 has the lowest impact. These results corroborate the previous associations between amounts of plasma sHLA-G levels and 3’UTR haplotypes in healthy individuals and reinforce that 3’UTR typing may be a predictor of the genetic predisposition of an individual to express different levels of HLA-G.

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Section: Discussionmentioning

confidence: 99%

Haplotypes of the HLA-G 3’ Untranslated Region Respond to Endogenous Factors of HLA-G+ and HLA-G- Cell Lines Differentially

et al. 2017

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“…The relationship between HLA-G 3′UTR polymorphisms (especially for the 14 bp polymorphism) and other variable sites in the HLA-G coding and promoter region was also previously explored [77, 78, 105, 112, 113]. Furthermore, several populations were evaluated regarding these polymorphic sites, including additional samples from other Brazilian regions and other worldwide populations, and the same pattern of 3′UTR variability has been observed [6, 27, 28, 85, 102, 114–121]. Recently, the variability at the HLA-G locus was explored by using the 1000 Genomes data [28, 102] and, taking together all of these studies in the last decade, it became clear that the same 3′UTR pattern observed in Brazilians [27] is found worldwide, with just some new low frequency haplotypes.…”

Section: Posttranscriptional Regulation Of Hla-gmentioning

confidence: 98%

Transcriptional and Posttranscriptional Regulations of theHLA-GGene

Castelli

Veiga‐Castelli

Yaghi

et al. 2014

Journal of Immunology Research

150

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HLA-G has a relevant role in immune response regulation. The overall structure of the HLA-G coding region has been maintained during the evolution process, in which most of its variable sites are synonymous mutations or coincide with introns, preserving major functional HLA-G properties. The HLA-G promoter region is different from the classical class I promoters, mainly because (i) it lacks regulatory responsive elements for IFN-γ and NF-κB, (ii) the proximal promoter region (within 200 bases from the first translated ATG) does not mediate transactivation by the principal HLA class I transactivation mechanisms, and (iii) the presence of identified alternative regulatory elements (heat shock, progesterone and hypoxia-responsive elements) and unidentified responsive elements for IL-10, glucocorticoids, and other transcription factors is evident. At least three variable sites in the 3′ untranslated region have been studied that may influence HLA-G expression by modifying mRNA stability or microRNA binding sites, including the 14-base pair insertion/deletion, +3142C/G and +3187A/G polymorphisms. Other polymorphic sites have been described, but there are no functional studies on them. The HLA-G coding region polymorphisms might influence isoform production and at least two null alleles with premature stop codons have been described. We reviewed the structure of the HLA-G promoter region and its implication in transcriptional gene control, the structure of the HLA-G 3′UTR and the major actors of the posttranscriptional gene control, and, finally, the presence of regulatory elements in the coding region.

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“…The +3187 A/G polymorphism is close to (4-bp upstream) an AU-rich motif and has been associated with decreased in vitro mRNA stability, so that the presence of the +3187A allele may lead to decreased HLA-G expression [15]. Recent studies have reported that the presence of the +3187 A allele is associated with preeclampsia in a Canadian population [15] and with systemic lupus erythematosus in Northeastern Brazilian patients [30]. …”

Section: Introductionmentioning

confidence: 99%

Polymorphic Sites at the 3’ Untranslated Region of the HLA-G Gene Are Associated with Differential hla-g Soluble Levels in the Brazilian and French Population

et al. 2013

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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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HLA-G 3′ Untranslated Region Polymorphisms Are Associated with Systemic Lupus Erythematosus in 2 Brazilian Populations

Abstract: These results indicate that HLA-G 3'UTR polymorphic sites, particularly +3142G and +3010C alleles, were associated with SLE susceptibility, whereas UTR-1 was associated with protection against development of SLE.

Cited by 34 publications

References 42 publications

Haplotypes of the HLA-G 3’ Untranslated Region Respond to Endogenous Factors of HLA-G+ and HLA-G- Cell Lines Differentially

Haplotypes of the HLA-G 3’ Untranslated Region Respond to Endogenous Factors of HLA-G+ and HLA-G- Cell Lines Differentially

Transcriptional and Posttranscriptional Regulations of theHLA-GGene

Polymorphic Sites at the 3’ Untranslated Region of the HLA-G Gene Are Associated with Differential hla-g Soluble Levels in the Brazilian and French Population

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