RESUMO
BACKGROUND: Chronic hepatitis C is characterized by a progressive deterioration of liver function and is involved in metabolic complications, such as hepatic steatosis. OBJECTIVE: The aim of this study was to investigate the role of host and viral characteristics associated with -493G/T (rs1800591), I128T (rs3816873), Q95H (rs61733139), and Q244E (rs17599091) Single Nucleotide Polymorphisms (SNPs) in the Microsomal Triglyceride Transfer Protein (MTTP) gene on hepatic steatosis in chronic hepatitis C. METHODS: SNPs were genotyped by PCR-RFLP and analyzed in combination with host and viral characteristics by multiple logistic regression in different genetic models of inheritance. RESULTS: The authors analyzed 236 patients with chronic hepatitis C, and 53% had hepatic steatosis. The mutated allele frequencies were > 5%, and the genotypes were in Hardy-Weinberg equilibrium (p ≥ 0.05). It was observed that patients with HCV genotype 3 infection (OR = 2.74, 95% CI 1.24â6.06, p = 0.013), female sex (OR = 2.28, 95% CI 1.21â4.28, p = 0.011) and moderate- and high-intensity liver inflammatory activity (A2-A3) (OR = 3.61, 95% CI 1.86â7.01, p < 0.001) alone exhibited a higher risk of steatosis. The results of multiple logistic regression analysis for interaction showed that for the -493G/T SNP, when the GT/TT genotype (dominant model) and the GT genotype (codominant model) were each combined with HCV genotype 3 infection, an 11.51-fold (95% CI 2.08â63.59, p = 0.005) and a 15.69-fold (95% CI 2.46â99.85, p = 0.004) increased risk of steatosis, respectively, was observed. For the I128T SNP, when both the IT/TT genotype (dominant model) and the IT genotype (codominant model) were combined with HCV genotype 3 infection, an 8.51-fold (95% CI 1.59â45.54, p = 0.012) and an 8.40 fold (95% CI 1.51â46.91, p = 0.015) increased risk of steatosis, respectively, was observed. CONCLUSION: The present study showed that the viral genotype combined with the -493G/T and I128T SNPs in the MTTP gene influences hepatic steatosis.
Assuntos
Proteínas de Transporte , Fígado Gorduroso , Hepatite C Crônica , Proteínas de Transporte/genética , Fígado Gorduroso/genética , Feminino , Genótipo , Hepacivirus , Hepatite C Crônica/genética , Humanos , Polimorfismo de Nucleotídeo Único , TriglicerídeosRESUMO
Abstract Background: Chronic hepatitis C is characterized by a progressive deterioration of liver function and is involved in metabolic complications, such as hepatic steatosis. Objective: The aim of this study was to investigate the role of host and viral characteristics associated with -493G/T (rs1800591), I128T (rs3816873), Q95H (rs61733139), and Q244E (rs17599091) Single Nucleotide Polymorphisms (SNPs) in the Microsomal Triglyceride Transfer Protein (MTTP) gene on hepatic steatosis in chronic hepatitis C. Methods: SNPs were genotyped by PCR-RFLP and analyzed in combination with host and viral characteristics by multiple logistic regression in different genetic models of inheritance. Results: The authors analyzed 236 patients with chronic hepatitis C, and 53% had hepatic steatosis. The mutated allele frequencies were > 5%, and the genotypes were in Hardy-Weinberg equilibrium (p ≥ 0.05). It was observed that patients with HCV genotype 3 infection (OR = 2.74, 95% CI 1.24‒6.06, p = 0.013), female sex (OR = 2.28, 95% CI 1.21‒4.28, p = 0.011) and moderate- and high-intensity liver inflammatory activity (A2-A3) (OR = 3.61, 95% CI 1.86‒7.01, p < 0.001) alone exhibited a higher risk of steatosis. The results of multiple logistic regression analysis for interaction showed that for the -493G/T SNP, when the GT/TT genotype (dominant model) and the GT genotype (codominant model) were each combined with HCV genotype 3 infection, an 11.51-fold (95% CI 2.08‒63.59, p = 0.005) and a 15.69-fold (95% CI 2.46‒99.85, p = 0.004) increased risk of steatosis, respectively, was observed. For the I128T SNP, when both the IT/TT genotype (dominant model) and the IT genotype (codominant model) were combined with HCV genotype 3 infection, an 8.51-fold (95% CI 1.59‒45.54, p = 0.012) and an 8.40 fold (95% CI 1.51‒46.91, p = 0.015) increased risk of steatosis, respectively, was observed. Conclusion: The present study showed that the viral genotype combined with the -493G/T and I128T SNPs in the MTTP gene influences hepatic steatosis.
RESUMO
Host single nucleotide polymorphisms (SNPs) in different genes can play a role in chronic hepatitis C virus (HCV) infection and influence the presence of hepatic fibrosis and comorbidities such as hepatic steatosis. We assessed the combined effect of SNPs in the PNPLA3, MTTP, TM6SF2, and IFNL3/IFNL4 genes in 288 Brazilian patients who were chronically infected with HCV. Hepatic fibrosis was observed in 246 (85.4%) patients and hepatic steatosis in 141 (49.0%) patients. PNPLA3 rs738409 (CG/GG) (Pâ¯=â¯0.044) and TM6SF2 rs58542926 (CT) (Pâ¯=â¯0.004) were alone associated with fibrosis, and PNPLA3 rs738409 (Pâ¯<â¯0.05, in distinct genetic models) was associated with steatosis. Multiple logistic regression of each SNP combined with HCV genotype 3 infection showed that MTTP rs1800591 (GT/TT) combined with HCV genotype 3 was associated with a 6.72-fold increased chance of hepatic steatosis (Pâ¯=â¯0.013). In the analysis of SNPs combined 2 by 2, no influence on hepatic fibrosis or steatosis was observed.
Assuntos
Fígado Gorduroso/genética , Hepatite C Crônica/genética , Cirrose Hepática/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Brasil , Proteínas de Transporte/genética , Fígado Gorduroso/virologia , Feminino , Estudos de Associação Genética , Genótipo , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C Crônica/virologia , Humanos , Interferons/genética , Lipase/genética , Cirrose Hepática/virologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-IdadeRESUMO
BACKGROUND: In chronic hepatitis C, the fibrosis progression rates are extremely variable and can be influenced by factors associated with the host, virus and environment. Among the associated metabolic factors, hepatic steatosis is characterized by an accumulation of triglycerides in hepatocytes. In the host, genetic determinants of hepatic steatosis are observed, such as single-nucleotide polymorphisms (SNPs) in the microsomal triglyceride transfer protein (MTTP) gene. The MTTP -493G/T SNP appears to play an important role in the regulation of gene expression and influences the plasma concentration of circulating low-density lipoprotein (LDL). The present study investigated the influence of this SNP in the development of hepatic steatosis in patients with chronic hepatitis C and evaluated the association of hepatic steatosis with certain characteristics of these patients and the hepatitis C virus (HCV). METHODS: Two hundred thirty-nine patients with chronic hepatitis C were genotyped for the MTTP -493G/T SNP by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The association between hepatic steatosis and selected characteristics of the patient and virus was evaluated using bivariate and multivariate analyses. RESULTS: The most prevalent MTTP -493G/T genotype was GG (46%) followed by GT (43.5%) and TT (10.5%). Multivariate analysis of the total cohort revealed associations between the presence of hepatic steatosis and inflammatory activity of moderate to high intensity (P < 0.001), advanced age (P = 0.010), elevated gamma glutamyl transpeptidase (GGT) levels (P = 0.010) and low LDL levels (P = 0.022). Hepatic steatosis was also associated with the TT/GT genotype of the MTTP -493G/T SNP in patients infected with HCV genotype 3 (P < 0.001). CONCLUSIONS: In chronic hepatitis C patients infected with HCV genotype 3 and with the TT/GT genotype of the MTTP -493G/T SNP, a significant increase in hepatic steatosis was observed, which may indicate that this SNP has a significant influence on the accumulation of triglycerides in hepatocytes. Furthermore, associations were observed between hepatic steatosis and inflammatory activity of moderate to high intensity, advanced age, elevated GGT and low LDL levels.
Assuntos
Proteínas de Transporte/genética , Fígado Gorduroso/genética , Fígado Gorduroso/virologia , Hepatite C Crônica/complicações , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Fígado Gorduroso/diagnóstico , Feminino , Marcadores Genéticos , Genótipo , Hepatite C Crônica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos RetrospectivosRESUMO
Non-alcoholic fatty liver disease (NAFLD) is intimately associated with insulin resistance and hypertriglyceridemia, whereas many of the mechanisms underlying this association are still poorly understood. In the present study, we investigated the relationship between microsomal triglyceride transfer protein (MTP) and markers of endoplasmic reticulum (ER) stress in the liver of rats subjected to neonatal monosodium L-glutamate (MSG)-induced obesity. At age 120 days old, the MSG-obese animals exhibited hyperglycemia, hypertriglyceridemia, insulin resistance, and liver steatosis, while the control (CTR) group did not. Analysis using fast protein liquid chromatography of the serum lipoproteins revealed that the triacylglycerol content of the very low-density lipoprotein (VLDL) particles was twice as high in the MSG animals compared with the CTR animals. The expression of ER stress markers, GRP76 and GRP94, was increased in the MSG rats, promoting a higher expression of X-box binding protein 1 (XBP-1), protein disulfide isomerase (PDI), and MTP. As the XBP-1/PDI/MTP axis has been suggested to represent a significant lipogenic mechanism in the liver response to ER stress, our data indicate that hypertriglyceridemia and liver steatosis occurring in the MSG rats are associated with increased MTP expression.