Regulatory Polymorphisms in the Interleukin‐18 Promoter Are Associated with Hepatitis C Virus Clearance

Laboratory of Genomic Diversity, Science Applications International Corportation-Frederick, MD, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 10/2008; 198(8):1159-65. DOI: 10.1086/592047
Source: PubMed


The immune response is critical in determining the outcome of hepatitis C virus (HCV) infection. Interleukin (IL)-18 is a pivotal mediator of the Th1/Th2-driven immune response. Two IL-18 promoter polymorphisms (-607C/A and -137G/C) and their haplotypes were known to affect IL-18 expression. We examined the role played by these polymorphisms in determining HCV clearance or persistence. Genotyping was performed among African American injection drug users with HCV clearance (n = 91) or HCV persistence (n = 182) and among European Americans with hemophilia who were mainly infected through plasma transfusion. Among injection drug users, IL18 -607A (odds ratio [OR], 3.68 [95% confidence interval {CI},1.85-7.34]) and IL18 -137C (OR, 2.33 [95% CI, 1.24-4.36]) were significantly associated with HCV clearance. A haplotype carrying -607A and -137C (OR, 4.53 [95% CI, 1.77-11.6]) was also strongly associated with viral clearance. No association was found among those with hemophilia. These results suggest that IL18 promoter polymorphism may affect the outcome of HCV infection in certain groups.

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Available from: Ping An, Apr 22, 2014
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    • "(IL)-18 is a pivotal mediator of the Th1/Th2-driven immune response. Two IL-18 promoter polymorphisms (−607C/A and −137G/C) and their haplotypes were known to affect IL-18 expression (Rehermann, 2009; An et al, 2008). Despite the potential implication of IL-18 promoter polymorphisms (−607C/A and −137G/C) in the pathogenesis of chronic hepatitis C virus infections, the association between IL-18 promoter polymorphisms (− 607C/A and − 137G/C) and chronic hepatitis C virus infections remains unclear. "
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    ABSTRACT: HCV infection has a chronicity rate of about 70%, several studies have shown that interleukin-18 (IL-18) was associated with etiology and progression of hepatitis C virus (HCV) infections. However, the association between single-nucleotide polymorphisms - 607C/A (rs1946518) and - 137G/C (rs187238) located in the IL-18 gene promoter and chronic hepatitis C virus infections was still controversial and ambiguous. To derive a more precise effect on the association between these polymorphisms and chronic hepatitis C virus infections, we performed this first meta-analysis based on the currently available evidence of the literature. A total of 4 studies with 1222 cases and 1115 controls for - 607C/A polymorphism and 3 studies with 959 cases and 987 controls for - 137G/C polymorphism were identified to perform a meta-analysis. Summary ORs and corresponding 95% CIs for IL-18 polymorphisms and chronic hepatitis C virus infections were estimated using fixed- and random-effects models when appropriate. Heterogeneity, sensitivity analysis, and publication bias were evaluated. We found a significant association between - 137G/C polymorphism and chronic hepatitis C virus infections (CG + CC versus GG: OR = 2.157, 95% CI [1.822, 2.553]; CC versus CG + GG: OR = 2.007, 95% CI [1.441, 2.797]). However, no significant association was observed between - 607C/A polymorphism and chronic hepatitis C virus infections under different contrast models. The present meta-analysis suggested that IL-18 - 137G/C polymorphism in promoter region was associated with chronic hepatitis C virus infections, but no evidence indicate association between - 607C/A polymorphism and chronic hepatitis C virus infections. High-quality studies with larger sample size and larger number are warranted.
    Meta Gene 09/2015; 5. DOI:10.1016/j.mgene.2015.04.004
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    • "IL-18 is a pivotal mediator of the Th1/Th2-driven immune response. IL-18 promoter polymorphisms (−607C/A and −137G/C) were found to be associated with SVC.42 "
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    ABSTRACT: Hepatitis C virus (HCV) has emerged as a major viral pandemic over the past two decades, infecting 170 million individuals, which equates to approximately 3% of the world's population. The prevalence of HCV varies according to geographic region, being highest in developing countries such as Egypt. HCV has a high tendency to induce chronic progressive liver damage in the form of hepatic fibrosis, cirrhosis, or liver cancer. To date, there is no vaccine against HCV infection. Combination therapy comprising PEGylated interferon-alpha and ribavirin has been the standard of care for patients with chronic hepatitis C for more than a decade. However, many patients still do not respond to therapy or develop adverse events. Recently, direct antiviral agents such as protease inhibitors, polymerase inhibitors, or NS5A inhibitors have been used to augment PEGylated interferon and ribavirin, resulting in better efficacy, better tolerance, and a shorter treatment duration. However, most clinical trials have focused on assessing the efficacy and safety of direct antiviral agents in patients with genotype 1, and the response of other HCV genotypes has not been elucidated. Moreover, the prohibitive costs of such triple therapies will limit their use in patients in developing countries where most of the HCV infection exists. Understanding the host and viral factors associated with viral clearance is necessary for individualizing therapy to maximize sustained virologic response rates, prevent progression to liver disease, and increase the overall benefits of therapy with respect to its costs. Genome wide studies have shown significant associations between a set of polymorphisms in the region of the interleukin-28B (IL28B) gene and natural clearance of HCV infection or after PEGylated interferon-alpha and ribavirin treatment with and without direct antiviral agents. This paper synthesizes the recent advances in the pharmacogenetics of HCV infection in the era of triple therapies.
    Hepatic Medicine: Evidence and Research 06/2014; 6:61-77. DOI:10.2147/HMER.S41127
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