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Regulatory polymorphisms in the interleukin-18 promoter are associated with hepatitis C virus clearance.

ABSTRACT: 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.

SUBMITTER: An P

PROVIDER: S-EPMC2674361 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Regulatory polymorphisms in the interleukin-18 promoter are associated with hepatitis C virus clearance.

An Ping P Thio Chloe L CL Kirk Gregory D GD Donfield Sharyne S Goedert James J JJ Winkler Cheryl A CA

The Journal of infectious diseases 20081001 8

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 persist ...[more]

PMID: 18781864

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Project description:BackgroundThe interleukin (IL)18 rs360719 CC genotype is associated with the development of antibodies to hepatitis B virus surface antigen (anti-HBs) in hemodialysis (HD) patients. IL18 shares biological properties with IL12 in promoting the T-hepler 1 (Th1) system. We studied whether polymorphisms in the IL12A 3` untranslated region (UTR) and IL12B 3`UTR may contribute to anti-HBs development (titre ≥ 10 IU/L) in HD patients either individually or jointly with the IL18 polymorphism.MethodsIn 518 HD patients and 240 controls the IL12A rs568408 3'UTR G > A polymorphism was genotyped by high-resolution melting curve analysis. Polymerase chain reaction restriction fragment length polymorphism was used to detect the IL12B rs3212227 3'UTR A > C and IL18 -1297 T > C rs360719 polymorphisms. The associations between the IL12A, IL12B and IL18 genotypes and the risk of impaired anti-HBs development were estimated by computing the odds ratios and their 95% confidence intervals using logistic regression analysis.ResultsIn the logistic regression analysis, the higher frequency of rs360719 CC individually (2.9% in 207 patients without anti-HBs development vs 8.0% in 311 patients with anti-HBs development, p = 0.009) and of rs360719 CC combined with rs568408 GG (p = 0.048), rs568408 GA (p = 0.035), rs568408 GG/AA (p = 0.034) or rs3212227 AA (p = 0.046) was associated with an increased chance for the development of anti-HBs in HD patients. Patients bearing both rs568408 AA and rs360719 TT had a 10.9-fold or 8.9-fold lower chance, respectively, to develop anti-HBs compared with those carrying any other genotype (p = 0.005) or those who had both wild-type rs568408 GG and rs360719 TT (p = 0.011). Carriers of both rs3212227 CC and rs360719 TC had a 4.6-fold lower chance for anti-HBs development than carriers of any other genotype (p = 0.042).ConclusionDevelopment of anti-HBs in HD patients is associated with gene polymorphisms of interleukins involved in the Th1 system.

Project description:UNLABELLED:The identification of associations between interleukin-28B (IL-28B) variants and the spontaneous clearance of hepatitis C virus (HCV) raises the issues of causality and the net contribution of host genetics to the trait. To estimate more precisely the net effect of IL-28B genetic variation on HCV clearance, we optimized genotyping and compared the host contributions in multiple- and single-source cohorts to control for viral and demographic effects. The analysis included individuals with chronic or spontaneously cleared HCV infections from a multiple-source cohort (n = 389) and a single-source cohort (n = 71). We performed detailed genotyping in the coding region of IL-28B and searched for copy number variations to identify the genetic variant or haplotype carrying the strongest association with viral clearance. This analysis was used to compare the effects of IL-28B variation in the two cohorts. Haplotypes characterized by carriage of the major alleles at IL-28B single-nucleotide polymorphisms (SNPs) were highly overrepresented in individuals with spontaneous clearance versus those with chronic HCV infections (66.1% versus 38.6%, P = 6 × 10(-9) ). The odds ratios for clearance were 2.1 [95% confidence interval (CI) = 1.6-3.0] and 3.9 (95% CI = 1.5-10.2) in the multiple- and single-source cohorts, respectively. Protective haplotypes were in perfect linkage (r(2) = 1.0) with a nonsynonymous coding variant (rs8103142). Copy number variants were not detected. CONCLUSION:We identified IL-28B haplotypes highly predictive of spontaneous HCV clearance. The high linkage disequilibrium between IL-28B SNPs indicates that association studies need to be complemented by functional experiments to identify single causal variants. The point estimate for the genetic effect was higher in the single-source cohort, which was used to effectively control for viral diversity, sex, and coinfections and, therefore, offered a precise estimate of the net host genetic contribution.

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Regulatory polymorphisms in the interleukin-18 promoter are associated with hepatitis C virus clearance.

Publications

Regulatory polymorphisms in the interleukin-18 promoter are associated with hepatitis C virus clearance.

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