functional SNP of interferon-γ gene is important for interferon-α-induced and spontaneous recovery from hepatitis C virus infection

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 3; pp. 985 - 990
• Main Authors: Huang, Ying, Yang, Huiying, Borg, Brian B, Su, Xiaowen, Rhodes, Shannon L, Yang, Kai, Tong, Xiaomei, Tang, George, Howell, Charles D, Rosen, Hugo R, Thio, Chloe L, Thomas, David L, Alter, Harvey J, Sapp, Ronda K, Liang, T. Jake
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 16.01.2007; National Acad Sciences
• Subjects: Alleles; Base Sequence; Biological Sciences; Carrier frequencies; Cytokines; Female; Fibrosis; Genes; Genotype; Genotypes; Hepatitis C - drug therapy; Hepatitis C - genetics; Hepatitis C virus; Histology; Humans; Infections; Interferon-alpha - therapeutic use; Interferon-gamma - genetics; Male; Middle Aged; Molecular Sequence Data; Oligonucleotide probes; Polymorphism, Single Nucleotide - genetics; Promoter regions; Promoter Regions, Genetic - genetics; T lymphocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0609954104

Cytokine polymorphisms are associated with disease outcome and interferon (IFN) treatment response in hepatitis C virus (HCV) infection. We genotyped eight SNPs spanning the entire IFN-γ gene in two cohorts and assessed the association between those polymorphisms and treatment response or spontaneous viral clearance. The first cohort was composed of 284 chronically HCV-infected patients who had received IFN-α-based therapy and the second was 251 i.v. drug users who had either spontaneously cleared HCV or become chronically infected. A SNP variant located in the proximal IFN-γ promoter region next to the binding motif of heat shock transcription factor (HSF), -764G, was significantly associated with sustained virological response [P = 0.04, odds ratio (OR) = 3.51 (confidence interval 1.0-12.5)]. The association was independently significant in multiple logistic regression (P = 0.04) along with race, viral titer, and genotype. This variant was also significantly associated with spontaneous recovery [P = 0.04, OR = 3.51 (1.0-12.5)] in the second cohort. Functional analyses show that the G allele confers a two- to three-fold higher promoter activity and stronger binding affinity to HSF1 than the C allele. Our study suggests that the IFN-γ promoter SNP -764G/C is functionally important in determining viral clearance and treatment response in HCV-infected patients and may be used as a genetic marker to predict sustained virological response in HCV-infected patients.