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Doctoral Thesis
DOI
https://doi.org/10.11606/T.5.2021.tde-17082021-094904
Document
Author
Full name
Karla Sawada Toda Oti
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2020
Supervisor
Committee
Oliveira, Claudia Pinto Marques Souza de (President)
Cazzo, Everton
Mazo, Daniel Ferraz de Campos
Teixeira, Andreza Corrêa
Title in Portuguese
Associação entre polimorfismos do gene da proteína desacopladora 3 (UCP3) com doença hepática gordurosa não alcoólica e síndrome metabólica
Keywords in Portuguese
Haplótipos
Hepatopatia gordurosa não alcoólica
Polimorfismo de nucleotídeo único
Proteína desacopladora 3
Síndrome metabólica
Abstract in Portuguese
Introdução: A doença hepática gordurosa não alcoólica (DHGNA) tem demonstrado um comportamento epidêmico. As variantes genéticas do gene da proteína desacopladora 3 (UCP3) foram associadas à obesidade, diabetes mellitus tipo 2 e perfil lipídico aterogênico, com resultados conflitantes. Nosso estudo avaliou a possível associação entre polimorfismos de nucleotídeo único (SNPs) do gene UCP3 com esteato-hepatite não alcoólica (EHNA) e síndrome metabólica (SM) em pacientes com DHGNA. Métodos: Foram selecionados 158 pacientes com DHGNA comprovada por biópsia hepática acompanhados entre 2010 e 2019 no Ambulatório de Doença hepática gordurosa não alcoólica do Hospital das Clínicas da Faculdade de Medicina de São Paulo (HCFMUSP). A partir de um banco de dados/DNA, os SNPs rs1726745, rs3781907 e rs11235972 do gene UCP3 foram genotipados. A amostra foi avaliada de acordo com a presença de esteatose ou EHNA e, de acordo com a presença de SM. A análise estatística foi realizada utilizando os softwares JMP, R e SHEsis. Resultados: A prevalência geral de SM foi 82,6% (n=128). Pacientes com EHNA (n=138) apresentaram maior frequência de SM (p=0,02), maior índice de massa corporal (IMC) (p=0,02) e maiores concentrações de aspartato aminotransferase (p=0,002). O genótipo TT do rs1726745 do gene UCP3 foi protetor para SM (OR=0,18; IC 95%=0,05-0,61; p=0,006) e associou-se à menor IMC na amostra geral (p=0,01) e no grupo EHNA (p=0,02). O alelo T do SNP rs1726745 associou-se com menores valores de AST (p=0,001), ALT (p=0,0002), TG (p=0,01) e colesterol total (p=0,02) na amostra geral. Na comparação entre grupos, houve menores valores de aminotransferases estritamente nos indivíduos com EHNA (AST, p=0,002; ALT, p=0,0007; vs esteatose) e com SM (AST, p=0,002; ALT, p=0,001; vs sem SM) e, menores valores de TG nos indivíduos com EHNA (p=0,02; vs esteatose). A presença do alelo G do SNP rs3781907 associou-se a menores valores de GGT (p=0,002) na amostra geral e nos grupos EHNA (p=0,004; vs esteatose) e com SM (p=0,003; vs sem SM) e com proteção para fibrose avançada (OR=0,25; IC 95%=0,08-0,69; p=0,01). O alelo A do SNP rs11235972 associou-se a menores valores de GGT (p=0,006) na amostra geral e nos grupos com EHNA (p=0,01; vs esteatose) e com SM (p=0,005; vs sem SM), com ausência de fibrose (OR=0,34; IC 95%=0,14-0,80; p=0,01) e proteção para fibrose avançada (OR=0,17; IC 95%=0,03-0,56; p=0,01). O haplótipo TAA (rs1726745, rs3781907, rs11235972) foi protetor para EHNA (OR=0,01; IC 95%=0,00-0,12; p=0,002) e o haplótipo TGG foi protetor para SM (OR=0,22; IC 95%=0,07-0,69; p=0,01). Conclusão: Variantes do gene UCP3 associaram-se à proteção para EHNA e SM, além de menores valores de enzimas hepáticas, perfil lipídico, IMC e menor gravidade da fibrose hepática na população estudada
Title in English
Association between UCP3 gene polymorphisms and nonalcoholic fatty liver disease and metabolic syndrome
Keywords in English
Metabolic syndrome
Non-alcoholic fatty liver disease
Polymorphism single nucleotide, Haplotypes
Uncoupling protein 3
Abstract in English
Introduction: Nonalcoholic fatty liver disease (NAFLD) has shown an epidemic behavior. Genetic variants in the uncoupling protein 3 (UCP3) gene have been associated with obesity, type 2 diabetes and atherogenic lipid profile, with conflicting results. Our study evaluated the possible association between UCP3 gene single nucleotide polymorphisms (SNPs) with nonalcoholic steatohepatitis (NASH) and metabolic syndrome (MetS) in NAFLD patients. Methods: UCP3 SNPs rs1726745, rs3781907 and rs11235972 were genotyped in 158 biopsyproven NAFLD patients. Subsequently, patients were evaluated according to the presence of nonalcoholic fatty liver (NAFL) or NASH and, according to the absence or presence of MetS. Statistics were performed with JMP, R and SHEsis software's. Results: The overall prevalence of MetS was 82.6% (n=128). NASH patients (n=138) had a higher MetS frequency (p=0.02), higher body mass index (BMI) (p=0.02) and higher concentrations of aspartate aminotransferase (AST) (p=0.002). The TT genotype of rs1726745 was protective for MetS (OR=0.18; 95% CI=0.05-0.61; p=0.006) and was associated with lower body mass index (BMI) in the general sample (p=0.01) and in the NASH group (p=0.02). The T allele of rs1726745 was associated with lower values of AST (p=0.001), ALT (p=0.0002), TG (p=0.01) and total cholesterol (p=0.02) in the general sample. In comparison between groups, there were lower values of aminotransferases strictly in individuals with NASH (AST, p=0.002; ALT, p=0.0007; vs NAFL) and with MetS (AST, p=0.002; ALT, p=0.001; vs without MetS). The G allele of rs3781907 was associated with lower GGT values (p=0.002) in the general sample and in the NASH group (p=0.004; vs NAFL) and with MetS group (p=0.003; vs without MetS) and, with protection for advanced fibrosis (OR=0.25; 95% CI=0.08-0.69; p=0.01).The A allele of rs11235972 was associated with lower GGT values (p=0.006) in the general sample and in the NASH group (p=0.01; vs NAFL) and with MetS group (p=0.005; vs without MetS), with fibrosis absence (OR=0.34; 95% CI=0.14-0.80; p=0.01) and protection for advanced fibrosis (OR=0.17; 95% CI=0.03-0.56; p=0.01). The TAA haplotype (rs1726745, rs3781907, rs11235972) was protective for NASH (OR=0.01; 95% CI=0.00-0.12; p=0.002) and TGG haplotype was protective for MetS (OR=0.22; 95% CI=0.07-0.69; p=0.01). Conclusion: UCP3 gene variants were associated with protection against NASH and MetS, in addition to lower values of liver enzymes, lipid profile, BMI and, lesser fibrosis severity in the studied population
 
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Publishing Date
2021-08-18
 
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