title: Genetic variation in STAT4 predicts response to interferon-α therapy for hepatitis B e antigen-positive chronic hepatitis B.
abstract: Interferon (IFN)-α is a first-line therapy for chronic hepatitis B (CHB) patients but only initiates a response in a minority of patients. A genetic variant, rs7574865 in STAT4, was recently reported to be associated with risk of developing CHB and hepatitis B virus-related hepatocellular carcinoma. We aimed to determine whether this variant is associated with the response to IFNα treatment for hepatitis B e antigen (HBeAg)-positive CHB patients. We studied 466 HBeAg-positive CHB patients who received either IFNα-2b (n = 224) or pegylated IFNα-2a (n = 242) therapy for 48 weeks and were followed for an additional 24 weeks. The rate of sustained virologic response (SVR), defined as HBeAg seroconversion along with hepatitis B virus DNA level <2000 copies/mL at week 72, was compared among patients with different genotypes of rs7574865. After 48 weeks of treatment and 24 weeks off treatment, the SVR rates in the IFNα-2b and pegylated IFNα-2a therapy groups were 30.4% and 28.9%, respectively. Compared to the rs7574865 GT/TT genotype, the GG genotype (a risk factor of CHB and hepatitis B virus-related hepatocellular carcinoma) was significantly associated with a reduced SVR rate in both patients who received IFNα-2b therapy (21.1% versus 37.2%, P = 0.01) and those who received pegylated IFNα-2a therapy (18.0% versus 41.2%, P = 9.74 × 10(-5) ). In joint analysis of the 466 patients, the GG genotype was associated with an approximately half SVR rate compared to the GT/TT genotype (19.3% versus 39.1%, P = 4.15 × 10(-6) ). A multivariate logistic regression model including rs7574865 and clinical variables showed that rs7574865 was the most significant factor for the prediction of SVR.
  
  
  CONCLUSIONS
  STAT4 rs7574865 is a reliable predictor of response to IFNα therapy for HBeAg-positive CHB patients and may be used for optimizing the treatment of CHB.
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, P.R. China.|Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, P.R. China.|Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, P.R. China.|Center for Genomic Translational Medicine and Prevention, Fudan University, Shanghai, P.R. China.|Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC.|Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL.|Pritzker School of Medicine, University of Chicago, Chicago, IL.
authors.forename: De-Ke
authors.initials: DK
authors.lastname: Jiang
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, P.R. China.
authors.forename: Xiaopan
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, P.R. China.|Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, P.R. China.
authors.forename: Ji
authors.initials: J
authors.lastname: Qian
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, P.R. China.
authors.forename: Xiao-Pin
authors.initials: XP
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, P.R. China.|Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, P.R. China.
authors.forename: Jingmin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Infectious Disease, Affiliated Youan Hospital, Capital University of Medical Science, Beijing, P.R. China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Xiamen Amoytop Biotech Co., Ltd., Xiamen, Fujian Province, P.R. China.
authors.forename: Runhua
authors.initials: R
authors.lastname: Wang
authors.affiliation: Xiamen Amoytop Biotech Co., Ltd., Xiamen, Fujian Province, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, P.R. China.|Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, P.R. China.|Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, P.R. China.|Center for Genomic Translational Medicine and Prevention, Fudan University, Shanghai, P.R. China.|Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC.|Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, P.R. China.|Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, P.R. China.|Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, P.R. China.|Center for Genomic Translational Medicine and Prevention, Fudan University, Shanghai, P.R. China.
authors.forename: Pengyin
authors.initials: P
authors.lastname: Zhang
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, P.R. China.
authors.forename: Xilin
authors.initials: X
authors.lastname: Zhu
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, P.R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Wu
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, P.R. China.
authors.forename: Kangmei
authors.initials: K
authors.lastname: Chen
authors.affiliation: Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL.
authors.forename: Carly
authors.initials: C
authors.lastname: Conran
authors.affiliation: Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC.|Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL.
authors.forename: S Lilly
authors.initials: SL
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, P.R. China.|Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, P.R. China.
authors.forename: Daru
authors.initials: D
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, P.R. China.|Institute of Biomedical Science, Fudan University, Shanghai, P.R. China.
authors.forename: Long
authors.initials: L
authors.lastname: Yu
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, P.R. China.|Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, P.R. China.|Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, P.R. China.|Center for Genomic Translational Medicine and Prevention, Fudan University, Shanghai, P.R. China.|Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC.|Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL.|Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
mesh_terms: D000328:Adult; D000368:Aged; D002681:China; D015331:Cohort Studies; D016001:Confidence Intervals; D016208:Databases, Factual; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation; D005838:Genotype; D006513:Hepatitis B e Antigens / Q000187:drug effects* / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D018570:Risk Assessment; D050797:STAT4 Transcription Factor / Q000235:genetics*; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
chemical_list: D006513:Hepatitis B e Antigens; D016898:Interferon-alpha; D050797:STAT4 Transcription Factor