title: A functional SNP of interferon-gamma gene is important for interferon-alpha-induced and spontaneous recovery from hepatitis C virus infection.
abstract: 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-gamma 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-alpha-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-gamma promoter region next to the binding motif of heat shock transcription factor (HSF), -764G, was significantly associated with sustained virological response [P = 0.01, odds ratio (OR) = 2.66 [corrected] (confidence interval 1.3-5.6)[corrected]]. 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-gamma 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.
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Huiying
authors.initials: H
authors.lastname: Yang
authors.forename: Brian B
authors.initials: BB
authors.lastname: Borg
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Su
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Rhodes
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Tong
authors.forename: George
authors.initials: G
authors.lastname: Tang
authors.forename: Charles D
authors.initials: CD
authors.lastname: Howell
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Rosen
authors.forename: Chloe L
authors.initials: CL
authors.lastname: Thio
authors.forename: David L
authors.initials: DL
authors.lastname: Thomas
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Alter
authors.forename: Ronda K
authors.initials: RK
authors.lastname: Sapp
authors.forename: T Jake
authors.initials: TJ
authors.lastname: Liang
mesh_terms: D000483:Alleles; D001483:Base Sequence; D005260:Female; D005838:Genotype; D006526:Hepatitis C / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D016898:Interferon-alpha; D007371:Interferon-gamma