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The association of toll-like receptor 4 polymorphism with hepatitis C virus infection in Saudi Arabian patients.

ABSTRACT: Hepatitis C virus (HCV) is a single stranded RNA virus. It affects millions of people worldwide and is considered as a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. A recent study reported that TLR4 gene polymorphisms are good prognostic predictors and are associated with protection from liver fibrosis among Caucasians. This study aims to investigate the implication of genetic polymorphisms of TLR4 gene on the HCV infection in Saudi Arabian patients. Two SNPs in the TLR4 gene, rs4986790 (A/G) and rs4986791 (C/T), were genotyped in 450 HCV patients and 600 uninfected controls. The association analysis confirmed that both SNPs showed a significant difference in their distribution between HCV-infected patients and uninfected control subjects (P < 0.0001; OR = 0.404, 95% CI = 0.281-0.581) and (P < 0.0001; OR = 0.298, 95% CI = 0.201-0.443), respectively. More importantly, haplotype analysis revealed that four haplotypes, AC, GT, GC, and AT (rs4986790, rs4986791), were significantly associated with HCV infection when compared with control subjects. One haplotype AC was more prominently found when chronic HCV-infected patients were compared with cirrhosis/HCC patients (frequency?=?94.7% and P = 0.04). Both TLR4 SNPs under investigation were found to be significantly implicated with HCV-infection among Saudi Arabian population.

SUBMITTER: Al-Qahtani AA

PROVIDER: S-EPMC4142570 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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The association of toll-like receptor 4 polymorphism with hepatitis C virus infection in Saudi Arabian patients.

Al-Qahtani Ahmed A AA Al-Anazi Mashael R MR Al-Zoghaibi Fahad F Abdo Ayman A AA Sanai Faisal M FM Khan Mohammed Q MQ Albenmousa Ali A Al-Ashgar Hamad I HI Al-Ahdal Mohammed N MN

BioMed research international 20140810

Hepatitis C virus (HCV) is a single stranded RNA virus. It affects millions of people worldwide and is considered as a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. A recent study reported that TLR4 gene polymorphisms are good prognostic predictors and are associated with protection from liver fibrosis among Caucasians. This study aims to investigate the implication of genetic polymorphisms of TLR4 gene on the HCV infection in Saudi Arabian patients. Two SNPs ...[more]

PMID: 25177689

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Project description:Hepatitis B virus (HBV) infection is a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. Human leukocyte antigens (HLAs) play an important role in the regulation of immune response against infectious organisms, including HBV. Recently, several genome-wide association (GWAS) studies have shown that genetic variations in HLA genes influence disease progression in HBV infection. The aim of this study was to investigate the role of HLA genetic polymorphisms and their possible role in HBV infection in Saudi Arabian patients. Variations in HLA genes were screened in 1672 subjects who were divided according to their clinical status into six categories as follows; clearance group, inactive carriers, active carriers, cirrhosis, hepatocellular carcinoma (HCC) patients and uninfected healthy controls. Three single nucleotide polymorphisms (SNPs) belonged to HLA-DQ region (rs2856718, rs7453920 and rs9275572) and two SNPs belonged to HLA-DP (rs3077 and rs9277535) were studied. The SNPs were genotyped by PCR-based DNA sequencing (rs2856718) and allele specific TaqMan genotyping assays (rs3077, rs7453920, rs9277535 and rs9275572). The results showed that rs2856718, rs3077, rs9277535 and rs9275572 were associated with HBV infection (p = 0.0003, OR = 1.351, CI = 1.147-1.591; p = 0.041, OR = 1.20, CI = 1.007-1.43; p = 0.045, OR = 1.198, CI = 1.004-1.43 and p = 0.0018, OR = 0.776, CI = 0.662-0.910, respectively). However, allele frequency of rs2856718, rs7453920 and rs9275572 were found more in chronically infected patients when compared to clearance group infection (p = 0.0001, OR = 1.462, CI = 1.204-1.776; p = 0.0178, OR = 1.267, CI = 1.042-1.540 and p = 0.010, OR = 0.776, CI = 0.639-0.942, respectively). No association was found when polymorphisms in HLA genes were compared in active carriers versus cirrhosis/HCC patients. In conclusion, these results suggest that variations in HLA genes could affect susceptibility to and clearance of HBV infection in Saudi Arabian patients.

Project description:Background:Inflammation is a fundamental factor that contributes to the development and progression of several types of cancer including colon cancer. Toll-like receptors (TLRs) and their signaling pathways have been reported to be associated with chronic inflammation and thereby induced cancer. Our aim was to investigate the expression and polymorphisms of TLR2 and their association with colon cancer. Methods:Real-time PCR and immunohistochemistry were used to investigate TLR2 gene expression and to evaluate the potential risk of predisposition to colon cancer caused by three tagging single-nucleotide polymorphisms (SNPs) on TLR2, including rs3804100, rs4696480, and rs3804099. TaqMan assay was conducted on samples from 115 patients with colon cancer and 102 age- and sex-matched normal individuals. Results:We found that, TLR2 was highly expressed in epithelial colon cancer cells and both TLR2 mRNA and protein levels, and significantly decreased in tumor tissues compared to normal tissues. Two of three TLR2 SNPs increased the risk of colon cancer. However, TLR2 rs3804099 increased the risk of colon cancer development by more than 3.8- and 5-fold in female patients and patients aged less than 57 years, respectively. The T allele of TLR2 rs3804100 showed a significant association with patients less than 57 years. In silico analysis of the TLR2 nucleotide substitution in SNP rs3804100 and rs3804099 determined that 67% and 70% probability of these single nucleotide variants alter splicing phenotypes, rs3804100 more specifically result on activating an additional splice site. Genotype and allele frequencies of rs4696480 were similar between the overall study populations. Thus, TLR2 rs4696480 appear to be not involved in colon cancer in our study population. Conclusions:There was a significant link between innate immunity deregulation through disruption of the TLRs and potential development of colon cancer. These SNPs can be used as screening markers for predicting colon cancer risk earlier in life to implement necessary prevention.

Project description:There are large gaps in understanding the molecular machinery accounting for the association of hepatitis C virus (HCV) infection with autoimmunity. Mixed cryoglobulinemia (MC) is the most common HCV-associated extrahepatic manifestation, which is characterized by B-cell lymphoproliferation and autoantibody production. B-cell activating factor (BAFF) is a member of the tumor necrosis factor family and plays an important role in B-cell proliferation. We explored the roles of hepatocyte-derived exosomal microRNAs (exo-miRNAs) and BAFF in the extrahepatic diseases of HCV infection. The exo-miRNA profiles were explored using a next-generation sequencing approach, followed by quantitative reverse transcription-PCR validation. The Toll-like receptor 7 (TLR7) polymorphism were analyzed using quantitative PCR. The biological function of exo-miRNAs and TLR7 polymorphism in BAFF expression was evaluated by using immunoblotting and enzyme-linked immunosorbent assay. Significantly increased levels of BAFF, exosomes, and TLR7 were found in HCV patients, particularly in those with MC (P < 0.005). HCV-infected hepatocyte-derived miR-122/let-7b/miR-206 upregulated BAFF expression in human macrophages through exosome transmission and TLR7 activation. Analysis of a TLR7 single-nucleotide polymorphism (rs3853839) revealed that G-allele carriers had increased TLR7 transcripts, resulting in more BAFF expression induced by hepatocyte-derived exo-miR-122, compared to those in C-allele carriers (P < 0.005). We identified HCV-infected hepatocyte-derived GU-enriched miRNAs (e.g., miR-122/let-7b/miR-206) as a TLR7 ligand that could induce BAFF production in macrophages through exosome transmission. The polymorphism in TLR7 is associated with the BAFF levels induced by exo-miR-122. It may be a potential predisposing factor of MC syndrome development. IMPORTANCE HCV remains an important cause of liver disease worldwide. Accumulating evidence has demonstrated that HCV infection is associated with B cell lymphoproliferative disorders such as MC. Approximately half of the patients infected with HCV develop MC, but the real reason and regulatory mechanism is still uncertain. Here, we demonstrate a novel relationship between HCV-infected hepatocyte-derived exo-miRNAs, host genetic background in TLR7, and BAFF expression. We validate that HCV-induced GU-enriched miRNAs (e.g., miR-122, let-7b, and miR-206) upregulated BAFF expression through exosome transmission and TLR7 activation. This mechanism of miRNAs action is implicated in HCV-infected hepatocyte-immune system communication and is important in extrahepatic manifestation development, thus representing a possible target for HCV infection and extrahepatic diseases treatment. In addition, we show that a functional polymorphism in TLR7 is a potential predisposing factor of MC development. Our results elucidate the molecular machinery in order to better understand the association of HCV infection with autoimmunity.

Dataset Information

The association of toll-like receptor 4 polymorphism with hepatitis C virus infection in Saudi Arabian patients.

Publications

The association of toll-like receptor 4 polymorphism with hepatitis C virus infection in Saudi Arabian patients.

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