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Master's Dissertation
DOI
https://doi.org/10.11606/D.25.2019.tde-27112019-182908
Document
Author
Full name
Jessica Lima Melchiades
Institute/School/College
Knowledge Area
Date of Defense
Published
Bauru, 2019
Supervisor
Committee
Garlet, Gustavo Pompermaier (President)
Buzalaf, Camila Peres
Neves, Lucimara Teixeira das
Rasmussen, Lucas Trevizani
Title in English
Impact of Slc11a1 gene variants on the host response patterns and in the determination of periodontal diseases resistance and susceptibility phenotypes
Keywords in English
Slc11a1 gene
Periodontal diseases
SNPs
Abstract in English
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.
Title in Portuguese
Impacto das variantes do gene Slc11a1 nos padrões de resposta do hospedeiro e na determinação de fenótipos de resistência e susceptibilidade às doenças periodontais
Keywords in Portuguese
Doença periodontal
Gene Slc11a1
SNPs
Abstract in Portuguese
Estudos em humanos e em modelos experimentais tem demonstrado a influência de múltiplos loci genéticos na determinação de fenótipos de susceptibilidade/resistência à periodontite. Dentre estes genes, o Slc11a1, cujas funções pleiotrópicas incluem a regulação da atividade macrófagos e linfócitos, tem potencial papel na modulação da resistência/susceptibilidade às doenças periodontais. Nesse contexto, nosso grupo demonstrou que camundongos das linhagens AIRmax e AIRmin, caracterizados pela predominância de variantes distintas de alelos do Slc11a1, associadas a diferentes padrões de resposta imune e inflamatória, apresentam fenótipos distintos de resistência/susceptibilidade à periodontite experimental. Ainda, variantes genéticas (SNPs) no Slc11a1 se mostram associadas a diferentes doenças infecciosas em humanos. Neste contexto, este estudo teve como objetivo correlacionar os polimorfismos genéticos rs17228995, rs17235409, rs2290708, rs2695343, rs3731865 do gene Slc11a1 com perfis de resistência/susceptibilidade às doenças periodontais em humanos, assim avaliar o impacto de variantes hipo/hiperresponsivas na periodontite experimental em camundongos. Para tanto, foram analisados 444 pacientes com periodontite crônica (CP), 476 indivíduos saudáveis (H) e 207 indivíduos com gengivite crônica (CG) para as análises de associação, e subgrupos para análise de possíveis correlações entre expressão/genótipo (CP=127, H=63) e para ensaios in vitro (H=29). Na análise dos genótipos, apenas os ensaios para a caracterização dos SNPs rs2290708 e rs37371865 se mostraram efetivos na descriminação alélica, os demais ensaios foram considerados tecnicamente inefetivos. Os polimorfismos rs2290708 e rs37371865 se mostraram associados ao risco de periodontite, sendo os genótipos CT+TT e GC+CC e alelos T e C (respectivamente) mais frequentes no grupo CP. Além da associação na abordagem caso controle, observamos que a presença dos alelos polimórficos T (rs2290708) e C (rs37371865) se mostrou associada ao aumento de expressão de TNF-, IL-1, IL-6, RANKL e RANKL/OPG nas lesões periodontais. Não foram observadas diferenças no padrão de colonização microbiológica de sítios com periodontite crônica com relação aos SNPs rs2290708 e rs37371865. A análise in vitro reforça a natureza hiper-reativa dos alelos polimórficos T (rs2290708) e C (rs37371865), uma vez que a produção de citocinas inflamatórias por macrófagos portadores de tais alelos se mostra aumentada frente ao estímulo por LPS. Finalmente, observamos que variantes hipereativas do Slc11a1, caracterizadas nas linhagens murinas AIRmin e AIRmax, se mostram associadas ao aumento de perda óssea alveolar, influxo de leucócitos e maior produção de citocinas pró-inflamatórias na periodontite experimental. Dessa forma, é possível concluir que polimorfismos funcionais no gene Slc11a1 associados ao aumento da responsividade inflamatória, e influenciam o risco ao desenvolvimento de periodontite em humanos e em modelo experimental.
 
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Release Date
2021-11-26
Publishing Date
2019-12-05
 
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