Impact of Toll-like Receptors 2(TLR2) and TLR 4 Gene Variations on HCV Susceptibility, Response to Treatment and Development of Hepatocellular Carcinoma in Cirrhotic HCV Patients.

Background and Aims: Genetic polymorphisms of Toll-like receptors (TLRs) have been proposed to affect susceptibility to HCV infection and progression to end-stage liver disease. This study was conducted to clarify the association of SNPS of TLR2 and TLR4 with clinical outcome of hepatitis C, response to treatment and development of HCC.Methods: The current study examined 3295 individuals from 725 families that were categorized into groups comprising chronic HCV (CH), spontaneous viral clearance (SC) and control subjects. Treated patients were classified into responders (RT) and non-responders (NRT). In addition, patients with liver cirrhotic (LC), and hepatocellular carcinoma (HCC) were also included. All subjects were genotyped for five single nucleotide polymorphisms (SNPs) of TLR2 and four SNPs of TLR4 and their haplotypes using allelic discrimination real-time PCR.Results: Results demonstrated strong association with allele A of rs13105517 of TLR2 and allele C of rs10116253 of TLR4 with CH in comparison to SC group. However, The peak of risk of HCC was observed with allele C of rs3804099 of TLR2 and C allele of rs10116253 TLR4 (p < 0.001).A strong association was found with allele T of rs1816702 of TLR2 and allele A of rs5030728 of TLR4 in non responder group in comparison to responders (p < 0.001). Haplotypes CAGT of TLR4 and ATAC of TLR2 showed significant association with CH and HCC groups in comparison to other groups.Conclusions: This study shows an association of minor alleles of TLR2 and TLR4 with outcome of HCV infection, response to therapy and development of HCC in cirrhotic patients.

Diagnosis of cirrhosis in patients with chronic hepatitis C genotype 4: Role of ABCB11 genotype polymorphism and plasma bile acid levels.

BACKGROUND/AIMS: Chronic hepatitis C (CHC)-related mortality generally results from cirrhosis and subsequent complications. We aimed to investigate the potential role of plasma bile acid levels and ABCB11 1331T > C (V444A, rs2287622) (ATP-binding cassette subfamily B, member 11) gene polymorphism in fibrosis prediction in CHC genotype 4 patients. MATERIALS AND METHODS: This case control study included 85 healthy control and the following 225 subjects: 170 adult patients infected with hepatitis C virus (HCV) and categorized into three groups according to liver biopsy; no fibrosis group (F0) (n=33), early fibrosis group (F1-F2) (n=61), and advanced fibrosis group (F3-F4) (n=76). Fasting bile acid levels, hepatitis C virus (HCV) genotyping, and ABCB11 1331T > C gene polymorphism were assessed. RESULTS: The frequency of the variant homozygote genotype CC in advanced fibrosis was significantly higher than that in early fibrosis (48.7% vs. 36.1%) (odd ratio, OR =2.58; 95% confidence interval, CI=1.07-6.20; p=0.03). C allele was significantly represented in advanced fibrosis (65.8%) compared with that in early fibrosis (51.6%) (OR=1.80, 95% CI=1.10-2.93, p=0.01). A significant elevation of plasma bile acid levels in advanced fibrosis was observed compared with those in early fibrosis (p≤0.001). Receiver operating characteristic curve for plasma bile acid levels at cutoff value of 75.5 µmol/L had a 59% specificity and 97.4% sensitivity as a predictor of advanced hepatic fibrosis (AUROC=0.78%). CONCLUSION: We concluded that Egyptian patients having chronic hepatitis C genotype 4 with CC genotype of ABCB11 SNP 1331T > C and high plasma bile acid levels at cutoff value of 75.5 µmol/L were associated with advanced hepatic fibrosis.