Genómica clínica na doença periodontal canina
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2018-10-12
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A doença periodontal engloba as afeções infecto-inflamatórias que afetam os tecidos que circundam e suportam os dentes e que designamos por periodonto. Inicialmente, manifestase numa forma reversível com halitose e edema, congestão e hemorragia da gengiva, a gengivite. Quando não tratada a inflamação progride para os tecidos mais profundos do suporte dentário, ocorrendo a sua destruição progressiva e a perda de adesão, conduzindo à perda das peças dentárias afetadas e atingindo-se a denominada fase de periodontite. Além disso, a doença periodontal pode afetar mais do que apenas a cavidade oral, sendo vista como um iniciador de graves consequências sistémicas. A etiologia desta doença é multifatorial, sendo a microbiota oral a principal causa para o despoletar desta doença. No entanto, vários outros fatores são apontados, nomeadamente fatores genéticos. Com base no facto de fatores genéticos contribuírem para o desenvolvimento desta doença, elegemos os recetores toll-like como genes candidatos. Os recetores toll-like são uma família de proteínas transmembranares responsáveis pelo reconhecimento de padrões moleculares associados a agentes patogénicos, presentes em microrganismos periodontopatogénicos, estimulando a resposta imunológica contra os mesmos. De forma a verificar a contribuição dos recetores toll-like para a progressão da doença periodontal, procedeu-se a uma revisão sistemática e meta-análise sobre a variante mais estudada (c.896A>G) presente no gene TLR4 humano. Além disso, foram analisadas um total de 68 variações genéticas dispersas pelas regiões exónicas dos 10 genes dos recetores toll-like caninos através de um estudo caso-controlo com uma população de 90 indivíduos, do quais 50 saudáveis e 40 casos. Entre as variantes analisadas no cão, quatro (rs852738689 no gene TLR6 e rs852069890, rs22882109 e rs22882111 no gene TLR9) mostraram diferenças estatisticamente significativas numa análise inicial. Após uma análise mais robusta – análise bootstrap – apenas uma não permaneceu associada à doença periodontal (rs852738689). As restantes três variantes estão localizadas no gene TLR9 e parecem ter um efeito na predisposição para a doença periodontal. Mais especificamente, no rs852069890, o genótipo AA confere proteção contra a doença periodontal; no rs22882109, a presença do alelo A está associada com o desenvolvimento desta doença; e no rs22882111, a presença do alelo T está associada com o desenvolvimento da doença periodontal, de acordo com a população agora estudada A identificação de biomarcadores pode ajudar a traçar perfis de suscetibilidade, identificando os indivíduos com maior predisposição para a doença e, consequentemente, permitir a implementação de estratégias preventivas mais eficientes e/ou terapias personalizadas. Assim, com este trabalho, verificou-se que a variante c.896A>G no gene TLR4 humano, não está associada com o desenvolvimento da doença periodontal no Homem, em contraste com os polimorfismos rs852069890, rs22882109 e rs22882111 presentes no gene TLR9 que poderão ser bons candidatos a biomarcadores na população canina. Nesse sentido, torna-se imperativo analisar estas variantes numa população mais alargada de forma a validar esta informação. E será igualmente interessante tentar esclarecer o efeito funcional destes polimorfismos.
Periodontal disease comprehends the infectious-inflammatory disorders that affect the tissues that surround and support the teeth – periodontium. Firstly, periodontal disease manifests in a reversible form where inflammation is confined to gingiva – gingivitis – occurring oedema, congestion, haemorrhage and halitosis. Without treatment, it can progress to periodontitis, where inflammation advances to the deeper tissues of the dental support, occurring the progressive destruction of these tissues and loss of adhesion, leading to the loss of dental pieces. Furthermore, periodontal disease can affect more than the oral cavity, being seen as an initiator of severe systemic consequences. The etiology of periodontal disease is multifactorial. Although the microbiota present in the oral cavity is considered the main cause of the onset of this disease, several other factors are pointed out, namely genetic factors. Based on the fact that genetic factors can contribute to the development of this disease, the toll-like receptors genes were chosen as candidates. Toll-like receptors constitute a transmembrane protein family responsible for recognizing pathogen-associated molecular patterns, present in periodontopathogenic microorganisms, stimulating the immune response. In order to verify the contribution of toll-like receptors genes for the progression of periodontal disease, a systematic review and meta-analysis of the most studied variant (c.896A> G) present in the human TLR4 gene was carried out. Furthermore, 68 genetic variations dispersed by the exonic regions of the 10 canine toll-like receptors genes were analyzed, in a case-control study using a population of 90 dogs (50 healthy and 40 cases). Only four of the sixty-eight variations (rs852738689 in the TLR6 gene and rs852069890, rs22882109 and rs22882111 in the TLR9 gene) showed statistically significant differences in a preliminary analysis. After performing a robust analysis – bootstrap analysis – only the genetic variation in the TLR6 gene did not remain associated with periodontal disease. The other three variants are located in the TLR9 gene and appear to have an effect on predisposition to periodontal disease. Particularly, in rs852069890, the AA genotype confers protection against periodontal disease; in rs22882109, the presence of the A allele is associated with the progress of this disease; and in rs22882111, the presence of the T allele is associated with the periodontal disease development, according to our population. The identification of biomarkers can help to establish susceptibility profiles, identifying individuals with predisposition for the disease and, consequently, allow the implementation of more effective preventive strategies and/or personalized therapies. Thus, according with this work, the c.896A> G variant in the human TLR4 gene has not been found to be associated with the development of periodontal disease in humans, in contrast to the rs852069890, rs22882109 and rs22882111 polymorphism in the canine TLR9 gene, which can be good candidates for biomarkers in the canine population. Therefore, it is imperative to analyze these genetic variations in a larger population in order to validate this information and clarify their functional effect.
Periodontal disease comprehends the infectious-inflammatory disorders that affect the tissues that surround and support the teeth – periodontium. Firstly, periodontal disease manifests in a reversible form where inflammation is confined to gingiva – gingivitis – occurring oedema, congestion, haemorrhage and halitosis. Without treatment, it can progress to periodontitis, where inflammation advances to the deeper tissues of the dental support, occurring the progressive destruction of these tissues and loss of adhesion, leading to the loss of dental pieces. Furthermore, periodontal disease can affect more than the oral cavity, being seen as an initiator of severe systemic consequences. The etiology of periodontal disease is multifactorial. Although the microbiota present in the oral cavity is considered the main cause of the onset of this disease, several other factors are pointed out, namely genetic factors. Based on the fact that genetic factors can contribute to the development of this disease, the toll-like receptors genes were chosen as candidates. Toll-like receptors constitute a transmembrane protein family responsible for recognizing pathogen-associated molecular patterns, present in periodontopathogenic microorganisms, stimulating the immune response. In order to verify the contribution of toll-like receptors genes for the progression of periodontal disease, a systematic review and meta-analysis of the most studied variant (c.896A> G) present in the human TLR4 gene was carried out. Furthermore, 68 genetic variations dispersed by the exonic regions of the 10 canine toll-like receptors genes were analyzed, in a case-control study using a population of 90 dogs (50 healthy and 40 cases). Only four of the sixty-eight variations (rs852738689 in the TLR6 gene and rs852069890, rs22882109 and rs22882111 in the TLR9 gene) showed statistically significant differences in a preliminary analysis. After performing a robust analysis – bootstrap analysis – only the genetic variation in the TLR6 gene did not remain associated with periodontal disease. The other three variants are located in the TLR9 gene and appear to have an effect on predisposition to periodontal disease. Particularly, in rs852069890, the AA genotype confers protection against periodontal disease; in rs22882109, the presence of the A allele is associated with the progress of this disease; and in rs22882111, the presence of the T allele is associated with the periodontal disease development, according to our population. The identification of biomarkers can help to establish susceptibility profiles, identifying individuals with predisposition for the disease and, consequently, allow the implementation of more effective preventive strategies and/or personalized therapies. Thus, according with this work, the c.896A> G variant in the human TLR4 gene has not been found to be associated with the development of periodontal disease in humans, in contrast to the rs852069890, rs22882109 and rs22882111 polymorphism in the canine TLR9 gene, which can be good candidates for biomarkers in the canine population. Therefore, it is imperative to analyze these genetic variations in a larger population in order to validate this information and clarify their functional effect.
Descrição
Dissertação de Mestrado em Genética Molecular, Comparativa e Tecnológica apresentada à Universidade de Trás-os-Montes e Alto Douro
Palavras-chave
Doença periodontal , Homem , Cão , Recetores toll-like , Polimorfismos