Tumor necrosis factor genetic polymorphisms and response to antiviral therapy in patients with chronic hepatitis C

Hugo R. Rosen, John G. McHutchison, Andrew J. Conrad, Jennifer J. Lentz, Gail Marousek, Steven L. Rose, Atif Zaman, Kent Taylor, Sunwen Chou

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE: Hepatitis C virus (HCV) is the major causal agent of non-A, non-B hepatitis and the leading indication for liver transplantation worldwide. The emerging field of immunogenetics has confirmed the significant role of heritability in host immune responses to infectious pathogens. Both the major and non-major histocompatibility complex genes are increasingly identified as candidate genes hypothesized to influence the susceptibility to, or the course of, a particular disease. We hypothesized that polymorphisms within the major histocompatibility complex class III region that encode for tumor necrosis factors (TNF)-α and TNF-β might be predictive of response to antiviral therapy in patients with chronic hepatitis C. METHODS: A total of 155 subjects, including 110 HCV-seropositive individuals undergoing antiviral therapy and 45 ethnically similar HCV-negative controls, were studied. The HCV-positive patients had undergone antiviral treatment with either interferon monotherapy (n = 73) or in combination with ribavirin (n = 37) and were categorized as either nonresponders, sustained responders, or relapsers. Sixty (55%) patients had genotype 1 (1a or 1b). Genomic DNA was extracted, followed by polymerase chain reaction amplification and sequencing for two promoter TNF-α variants (at positions -238 and -308), as well as restriction fragment length analysis for four polymorphic loci within the TNF-β gene (NcoI, TNFc, aa13, aa26). RESULTS: Although there was a trend toward higher frequency of the A allele in the TNF 238 promoter among HCV-infected patients (12% vs 4%), there were no significant differences in the distribution of the genotypic polymorphisms between patients and controls. Patients with the TNF 238 A allele had higher pretreatment viral loads as compared with patients homozygous for the wild type allele (7.2 × 106 ± 4.2 × 106 copies/ml vs 3.8 × 106 ± 0.34 × 106 copies/ml, p = 0.03). However, there was no association between TNF genetic markers, including multiple haplotypic combinations, and response to therapy. In addition, there was no correlation with these polymorphic loci and histological severity of liver disease. CONCLUSIONS: Although previous work has suggested potential roles for TNF in the pathogenesis of HCV infection, we were unable to identify any link between TNF genetic polymorphisms and histological severity or response to antiviral therapy.

Original languageEnglish (US)
Pages (from-to)714-720
Number of pages7
JournalAmerican Journal of Gastroenterology
Volume97
Issue number3
DOIs
StatePublished - 2002
Externally publishedYes

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Tumor Necrosis Factors
Genetic Polymorphisms
Chronic Hepatitis C
Antiviral Agents
Tumor Necrosis Factor-alpha
Hepacivirus
Therapeutics
Major Histocompatibility Complex
Alleles
Genes
Immunogenetics
Ribavirin
Virus Diseases
Viral Load
Genetic Markers
Gene Frequency
Liver Transplantation
Interferons
Hepatitis
Liver Diseases

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Tumor necrosis factor genetic polymorphisms and response to antiviral therapy in patients with chronic hepatitis C. / Rosen, Hugo R.; McHutchison, John G.; Conrad, Andrew J.; Lentz, Jennifer J.; Marousek, Gail; Rose, Steven L.; Zaman, Atif; Taylor, Kent; Chou, Sunwen.

In: American Journal of Gastroenterology, Vol. 97, No. 3, 2002, p. 714-720.

Research output: Contribution to journalArticle

Rosen, Hugo R. ; McHutchison, John G. ; Conrad, Andrew J. ; Lentz, Jennifer J. ; Marousek, Gail ; Rose, Steven L. ; Zaman, Atif ; Taylor, Kent ; Chou, Sunwen. / Tumor necrosis factor genetic polymorphisms and response to antiviral therapy in patients with chronic hepatitis C. In: American Journal of Gastroenterology. 2002 ; Vol. 97, No. 3. pp. 714-720.
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abstract = "OBJECTIVE: Hepatitis C virus (HCV) is the major causal agent of non-A, non-B hepatitis and the leading indication for liver transplantation worldwide. The emerging field of immunogenetics has confirmed the significant role of heritability in host immune responses to infectious pathogens. Both the major and non-major histocompatibility complex genes are increasingly identified as candidate genes hypothesized to influence the susceptibility to, or the course of, a particular disease. We hypothesized that polymorphisms within the major histocompatibility complex class III region that encode for tumor necrosis factors (TNF)-α and TNF-β might be predictive of response to antiviral therapy in patients with chronic hepatitis C. METHODS: A total of 155 subjects, including 110 HCV-seropositive individuals undergoing antiviral therapy and 45 ethnically similar HCV-negative controls, were studied. The HCV-positive patients had undergone antiviral treatment with either interferon monotherapy (n = 73) or in combination with ribavirin (n = 37) and were categorized as either nonresponders, sustained responders, or relapsers. Sixty (55{\%}) patients had genotype 1 (1a or 1b). Genomic DNA was extracted, followed by polymerase chain reaction amplification and sequencing for two promoter TNF-α variants (at positions -238 and -308), as well as restriction fragment length analysis for four polymorphic loci within the TNF-β gene (NcoI, TNFc, aa13, aa26). RESULTS: Although there was a trend toward higher frequency of the A allele in the TNF 238 promoter among HCV-infected patients (12{\%} vs 4{\%}), there were no significant differences in the distribution of the genotypic polymorphisms between patients and controls. Patients with the TNF 238 A allele had higher pretreatment viral loads as compared with patients homozygous for the wild type allele (7.2 × 106 ± 4.2 × 106 copies/ml vs 3.8 × 106 ± 0.34 × 106 copies/ml, p = 0.03). However, there was no association between TNF genetic markers, including multiple haplotypic combinations, and response to therapy. In addition, there was no correlation with these polymorphic loci and histological severity of liver disease. CONCLUSIONS: Although previous work has suggested potential roles for TNF in the pathogenesis of HCV infection, we were unable to identify any link between TNF genetic polymorphisms and histological severity or response to antiviral therapy.",
author = "Rosen, {Hugo R.} and McHutchison, {John G.} and Conrad, {Andrew J.} and Lentz, {Jennifer J.} and Gail Marousek and Rose, {Steven L.} and Atif Zaman and Kent Taylor and Sunwen Chou",
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T1 - Tumor necrosis factor genetic polymorphisms and response to antiviral therapy in patients with chronic hepatitis C

AU - Rosen, Hugo R.

AU - McHutchison, John G.

AU - Conrad, Andrew J.

AU - Lentz, Jennifer J.

AU - Marousek, Gail

AU - Rose, Steven L.

AU - Zaman, Atif

AU - Taylor, Kent

AU - Chou, Sunwen

PY - 2002

Y1 - 2002

N2 - OBJECTIVE: Hepatitis C virus (HCV) is the major causal agent of non-A, non-B hepatitis and the leading indication for liver transplantation worldwide. The emerging field of immunogenetics has confirmed the significant role of heritability in host immune responses to infectious pathogens. Both the major and non-major histocompatibility complex genes are increasingly identified as candidate genes hypothesized to influence the susceptibility to, or the course of, a particular disease. We hypothesized that polymorphisms within the major histocompatibility complex class III region that encode for tumor necrosis factors (TNF)-α and TNF-β might be predictive of response to antiviral therapy in patients with chronic hepatitis C. METHODS: A total of 155 subjects, including 110 HCV-seropositive individuals undergoing antiviral therapy and 45 ethnically similar HCV-negative controls, were studied. The HCV-positive patients had undergone antiviral treatment with either interferon monotherapy (n = 73) or in combination with ribavirin (n = 37) and were categorized as either nonresponders, sustained responders, or relapsers. Sixty (55%) patients had genotype 1 (1a or 1b). Genomic DNA was extracted, followed by polymerase chain reaction amplification and sequencing for two promoter TNF-α variants (at positions -238 and -308), as well as restriction fragment length analysis for four polymorphic loci within the TNF-β gene (NcoI, TNFc, aa13, aa26). RESULTS: Although there was a trend toward higher frequency of the A allele in the TNF 238 promoter among HCV-infected patients (12% vs 4%), there were no significant differences in the distribution of the genotypic polymorphisms between patients and controls. Patients with the TNF 238 A allele had higher pretreatment viral loads as compared with patients homozygous for the wild type allele (7.2 × 106 ± 4.2 × 106 copies/ml vs 3.8 × 106 ± 0.34 × 106 copies/ml, p = 0.03). However, there was no association between TNF genetic markers, including multiple haplotypic combinations, and response to therapy. In addition, there was no correlation with these polymorphic loci and histological severity of liver disease. CONCLUSIONS: Although previous work has suggested potential roles for TNF in the pathogenesis of HCV infection, we were unable to identify any link between TNF genetic polymorphisms and histological severity or response to antiviral therapy.

AB - OBJECTIVE: Hepatitis C virus (HCV) is the major causal agent of non-A, non-B hepatitis and the leading indication for liver transplantation worldwide. The emerging field of immunogenetics has confirmed the significant role of heritability in host immune responses to infectious pathogens. Both the major and non-major histocompatibility complex genes are increasingly identified as candidate genes hypothesized to influence the susceptibility to, or the course of, a particular disease. We hypothesized that polymorphisms within the major histocompatibility complex class III region that encode for tumor necrosis factors (TNF)-α and TNF-β might be predictive of response to antiviral therapy in patients with chronic hepatitis C. METHODS: A total of 155 subjects, including 110 HCV-seropositive individuals undergoing antiviral therapy and 45 ethnically similar HCV-negative controls, were studied. The HCV-positive patients had undergone antiviral treatment with either interferon monotherapy (n = 73) or in combination with ribavirin (n = 37) and were categorized as either nonresponders, sustained responders, or relapsers. Sixty (55%) patients had genotype 1 (1a or 1b). Genomic DNA was extracted, followed by polymerase chain reaction amplification and sequencing for two promoter TNF-α variants (at positions -238 and -308), as well as restriction fragment length analysis for four polymorphic loci within the TNF-β gene (NcoI, TNFc, aa13, aa26). RESULTS: Although there was a trend toward higher frequency of the A allele in the TNF 238 promoter among HCV-infected patients (12% vs 4%), there were no significant differences in the distribution of the genotypic polymorphisms between patients and controls. Patients with the TNF 238 A allele had higher pretreatment viral loads as compared with patients homozygous for the wild type allele (7.2 × 106 ± 4.2 × 106 copies/ml vs 3.8 × 106 ± 0.34 × 106 copies/ml, p = 0.03). However, there was no association between TNF genetic markers, including multiple haplotypic combinations, and response to therapy. In addition, there was no correlation with these polymorphic loci and histological severity of liver disease. CONCLUSIONS: Although previous work has suggested potential roles for TNF in the pathogenesis of HCV infection, we were unable to identify any link between TNF genetic polymorphisms and histological severity or response to antiviral therapy.

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