Investigação de polimorfismos genéticos e metabolismo lipídico com doença periodontal crônica: metanálise e estudo caso-controle
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Data
2018-03-28
Autores
Oliveira, Rafael Nepomuceno [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Diversos fatores relacionados ao hospedeiro, como fatores ambientais (tabagismo), doenças sistêmicas (diabetes e dislipidemia) e herança genética vêm sendo estudados quanto à influência no início e progressão da doença periodontal. Embora muitos estudos tenham investigado a relação entre dislipidemia e periodontite crônica (PC), examinando os níveis séricos de lipídeos, os resultados ainda são contraditórios, indicando a demanda da realização de uma metanálise. Alguns Genome-Wide Association Studies (GWAS), estudos de bioinformática e diversos estudos caso-controle evidenciaram variantes genéticas associadas à suscetibilidade à periodontite, mas os resultados para alguns desses polimorfismos são escassos ou contraditórios entre as diferentes populações. Assim, nota-se a importância de realizar metanálises e estudos caso-controle para buscar validar ou identificar a associação de polimorfismos com a PC na população brasileira. O objetivo deste estudo foi dividido em 3 capítulos: (1) investigar se os pacientes com PC apresentam diferentes níveis séricos de parâmetros lipídicos (HDL, LDL, colesterol total e triglicérides) em comparação com indivíduos saudáveis; (2) avaliar se polimorfismos de base única (SNPs, single nucleotide polymorphisms) nos genes LDLR (rs5925 e rs688) e APOB (rs676210 e rs693) contribuem para a suscetibilidade à PC, uma vez que PC está associada a níveis plasmáticos de LDL mais elevados, e os polimorfismos nestes genes podem aumentar as concentrações plasmáticas de LDL; (3) validar na população brasileira a associação de polimorfismos genéticos previamente associados à PC em outras populações, por meio de estudos que utilizaram técnicas sofisticadas de bioinformática e GWAS. No capítulo (1), foi realizada uma revisão sistemática com metanálise e meta-regressão. Nos capítulos (2) e (3) foram realizados estudos caso-controle com genotipagem de SNPs em pacientes com e sem PC para investigar a associação destes SNPs entre os diferentes genótipos em relação a PC e parâmetros periodontais, além de avaliar a associação genética sexo-específica, e a da interação destas variações genéticas com fatores ambientais (tabagismo). Na metanálise, foram incluídas 19 publicações, verificando-se como resultado que os participantes com PC apresentaram níveis séricos significativamente elevados de LDL e triglicerídeos (p = 0,003 e p <0,0001, respectivamente) e níveis significativamente mais baixos de HDL (p = 0,0005), comparando- se a indivíduos sem PC. Como resultado do capítulo (2), não foi verificada associação significativa entre os parâmetros clínicos periodontais e as frequências de genótipos de qualquer dos SNPs nos genes APOB e LDLR avaliados. Comparando-se pacientes com e sem PC, não houve diferenças significativas em nenhuma das análises multivariadas, interações multiplicativas e aditivas entre cada SNP e tabagismo e frequência de haplótipos nos dois genes. Referente ao capítulo (3), constatou-se que os SNPs rs2521634 (próximo ao gene NPY) e rs3811046 (no gene IL37) foram validados na população brasileira estudada como associado à PC. Em conclusão, observou-se que a PC foi associada a níveis mais altos de LDL e triglicérides, e níveis mais baixos de HDL; enquanto que não foi associada aos SNPs estudados nos genes LDLR e APOB; mas houve validação na população brasileira estudada dos SNPs próximo ao gene NPY e no gene IL37, previamente identificados por GWAS, com associação de maior risco à PC severa e moderada.
Several factors related to the host, such as environmental factors (smoking), systemic diseases (diabetes and dyslipidemia) and genetic inheritance have been studied regarding the influence on the onset and progression of periodontal disease. Although several studies have investigated the relationship between dyslipidemia and chronic periodontitis (CP), focusing on serum lipid levels, the results are still contradictory, indicating the necessity of a meta-analysis. Some genome-wide association studies (GWAS), bioinformatics studies and several case-control studies have shown genetic variants associated with susceptibility to CP, but the results of some of these polymorphisms are sparse and contradictory among different populations. Thus, it is important to conduct meta-analysis and case-control studies in order to validate or identify an association of polymorphisms with CP in a Brazilian population. The objective of this study was divided into three chapters: (1) to investigate whether patients with CP present different serum levels of lipid parameters (HDL, LDL, total cholesterol and triglycerides) compared to healthy individuals; (2) to assess whether single nucleotide polymorphisms (SNPs) in the LDLR (rs5925 and rs688) and APOB (rs676210 and rs693) genes contribute to CP susceptibility, since CP is associated with higher plasma LDL levels and the polymorphisms of these genes may increase plasma LDL concentration; (3) to validate, in the Brazilian population, the association of genetic polymorphisms previously associated with CP in other populations, through studies using sophisticated bioinformatics techniques and GWAS. A systematic review with meta- analysis and meta-regression was performed in chapter (1). Case-control studies with genotyping of SNPs in patients with and without CP were performed in chapters (2) and (3). These studies was conducted to investigate the association of different SNPs genotypes respecting to CP and periodontal parameters, as well as to evaluate sex-specific genetic association, and gene-environmental interaction. In the meta-analysis, 19 publications were included. It was found that participants with CP had significant higher LDL and triglycerides serum levels (p = 0.003 and p < 0.0001, respectively) and lower HDL levels (p = 0.0005) compared to healthy patients. As a result of chapter (2), no significant association was found between the periodontal clinical parameters and the frequencies of genotypes of any of the SNPs in the APOB and LDLR genes evaluated. Comparing patients with and without CP, there were no significant differences in any multivariate analysis, multiplicative and additive interactions between each SNP and smoking and haplotype frequency in the two genes. Regarding chapter (3), the rs2521634 (near the NPY gene) and rs3811046 (in the IL37 gene) SNPs were validated in the Brazilian population studied in association with CP. In conclusion, CP was associated with higher levels of LDL and triglycerides and lower levels of HDL; while it was not associated with the SNPs studied in the LDLR and APOB genes; but there was validation in the studied Brazilian population of the SNPs near to the NPY gene and in the IL37 gene with a higher risk association to severe and moderate CP, previously identified by the GWAS.
Several factors related to the host, such as environmental factors (smoking), systemic diseases (diabetes and dyslipidemia) and genetic inheritance have been studied regarding the influence on the onset and progression of periodontal disease. Although several studies have investigated the relationship between dyslipidemia and chronic periodontitis (CP), focusing on serum lipid levels, the results are still contradictory, indicating the necessity of a meta-analysis. Some genome-wide association studies (GWAS), bioinformatics studies and several case-control studies have shown genetic variants associated with susceptibility to CP, but the results of some of these polymorphisms are sparse and contradictory among different populations. Thus, it is important to conduct meta-analysis and case-control studies in order to validate or identify an association of polymorphisms with CP in a Brazilian population. The objective of this study was divided into three chapters: (1) to investigate whether patients with CP present different serum levels of lipid parameters (HDL, LDL, total cholesterol and triglycerides) compared to healthy individuals; (2) to assess whether single nucleotide polymorphisms (SNPs) in the LDLR (rs5925 and rs688) and APOB (rs676210 and rs693) genes contribute to CP susceptibility, since CP is associated with higher plasma LDL levels and the polymorphisms of these genes may increase plasma LDL concentration; (3) to validate, in the Brazilian population, the association of genetic polymorphisms previously associated with CP in other populations, through studies using sophisticated bioinformatics techniques and GWAS. A systematic review with meta- analysis and meta-regression was performed in chapter (1). Case-control studies with genotyping of SNPs in patients with and without CP were performed in chapters (2) and (3). These studies was conducted to investigate the association of different SNPs genotypes respecting to CP and periodontal parameters, as well as to evaluate sex-specific genetic association, and gene-environmental interaction. In the meta-analysis, 19 publications were included. It was found that participants with CP had significant higher LDL and triglycerides serum levels (p = 0.003 and p < 0.0001, respectively) and lower HDL levels (p = 0.0005) compared to healthy patients. As a result of chapter (2), no significant association was found between the periodontal clinical parameters and the frequencies of genotypes of any of the SNPs in the APOB and LDLR genes evaluated. Comparing patients with and without CP, there were no significant differences in any multivariate analysis, multiplicative and additive interactions between each SNP and smoking and haplotype frequency in the two genes. Regarding chapter (3), the rs2521634 (near the NPY gene) and rs3811046 (in the IL37 gene) SNPs were validated in the Brazilian population studied in association with CP. In conclusion, CP was associated with higher levels of LDL and triglycerides and lower levels of HDL; while it was not associated with the SNPs studied in the LDLR and APOB genes; but there was validation in the studied Brazilian population of the SNPs near to the NPY gene and in the IL37 gene with a higher risk association to severe and moderate CP, previously identified by the GWAS.
Descrição
Palavras-chave
Periodontite crônica, Dislipidemias, Metanálise, Polimorfismo genético, Genótipo, Chronic periodontitis, Dyslipidemias, Meta-analysis, Genetic polymorphism, Genotype