Impact of Slc11a1 gene variants on the host response patterns and in the determination of periodontal diseases resistance and susceptibility phenotypes

• Ano de defesa: 2019
• Autor(a) principal: Melchiades, Jessica Lima
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: eng
• Instituição de defesa: Biblioteca Digitais de Teses e Dissertações da USP
• Palavras-chave em Português: Slc11a1 gene; Doença periodontal; Gene Slc11a1; Periodontal diseases; SNPs
• Link de acesso: http://www.teses.usp.br/teses/disponiveis/25/25149/tde-27112019-182908/

Studies in humans and experimental models have demonstrated the influence of multiple genetic loci on the determination of susceptibility/resistance phenotypes to periodontitis. Among these genes, Slc11a1, whose pleiotropic functions include the regulation of macrophages and lymphocyte activity, has a potential role in the modulation of resistance/susceptibility to periodontal diseases. In this context, our group demonstrated that AIRmax and AIRmin mice, characterized by the predominance of distinct variants of Slc11a1 alleles, associated to different patterns of immune and inflammatory response, present distinct phenotypes of resistance/susceptibility to experimental periodontitis. Furthermore, genetic variants (SNPs) in Slc11a1 are shown to be associated with different infectious diseases in humans. In this context, this study aimed to correlate the genetic polymorphisms rs17228995, rs17235409, rs2290708, rs2695343, rs3731865 of the gene Slc11a1 with profiles of resistance/susceptibility to periodontal diseases in humans, thus to evaluate the impact of hypo/hyperresponsive variants on experimental periodontitis in mice. Forty-five patients with chronic periodontitis (CP), 476 healthy individuals (H) and 207 individuals with chronic gingivitis (CG) were analyzed for association analysis, and subgroups were analyzed for analysis of possible correlations between expression / genotype (CP = 127, H = 63) and for in vitro tests (H = 29). In the analysis of the genotypes, only the assays for the characterization of the SNPs rs2290708 and rs3731865 were effective in the allelic discrimination, the other tests were considered technically ineffective. The polymorphisms rs2290708 and rs3731865 were shown to be associated with the risk of periodontitis, with a higher frequency of the genotypes CT+TT and GC+CC and the alleles T and C (respectively) in the CP group. In addition to the association in the control case approach, the presence of the polymorphic T (rs2290708) and C (rs37371865) alleles was shown to be associated with increased TNF-, IL-1, IL-6, RANKL and RANKL/OPG periodontal lesions. No differences were observed in the pattern of microbiological colonization of sites with chronic periodontitis with respect to the SNPs rs2290708 and rs37371865. In vitro analysis reinforces the hyper-reactive nature of the polymorphic alleles T (rs2290708) and C (rs37371865), since the production of inflammatory cytokines by macrophages bearing such alleles is shown to be increased in response to LPS stimulation. Finally, we observed that hyperreactive variants of Slc11a1, characterized in the AIRmin and AIRmax murine are associated with increased alveolar bone loss, leukocyte influx, and increased production of proinflammatory cytokines in experimental periodontitis. Thus, it is possible to conclude that functional polymorphisms in the Slc11a1 gene, associated with increased inflammatory responsiveness, influence the risk to the development of periodontitis in humans and in mice experimental model.