title: Genetic variants in five novel loci including CFB and CD40 predispose to chronic hepatitis B.
abstract: Hepatitis B virus affects more than 2 billion people worldwide, 350 million of which have developed chronic hepatitis B (CHB). The genetic factors that confer CHB risk are still largely unknown. We sought to identify genetic variants for CHB susceptibility in the Chinese population. We undertook a genome-wide association study (GWAS) in 2,514 CHB cases and 1,130 normal controls from eastern China. We replicated 33 of the most promising signals and eight previously reported CHB risk loci through a two-stage validation totaling 6,600 CHB cases and 8,127 controls in four independent populations, of which two populations were recruited from eastern China, one from northern China and one from southern China. The joint analyses of 9,114 CHB cases and 9,257 controls revealed significant association of CHB risk with five novel loci. Four loci are located in the human leukocyte antigen (HLA) region at 6p21.3, including two nonsynonymous variants (rs12614 [R32W] in complement factor B [CFB], Pmeta =1.28 × 10(-34) ; and rs422951 [T320A] in NOTCH4, Pmeta  = 5.33 × 10(-16) ); one synonymous variant (rs378352 in HLA-DOA corresponding to HLA-DOA*010101, Pmeta  = 1.04 × 10(-23) ); and one noncoding variant (rs2853953 near HLA-C, Pmeta  = 5.06 × 10(-20) ). Another locus is located at 20q13.1 (rs1883832 in the Kozak sequence of CD40, Pmeta  = 2.95 × 10(-15) ). Additionally, we validated seven of eight previously reported CHB susceptibility loci (rs3130542 at HLA-C, rs1419881 at TCF19, rs652888 at EHMT2, rs2856718 at HLA-DQB1, rs7453920 at HLA-DQB2, rs3077 at HLA-DPA1, and rs9277535 at HLA-DPA2, which are all located in the HLA region, 9.84 × 10(-71)  ≤ Pmeta  ≤ 9.92 × 10(-7) ).
  
  
  CONCLUSIONS
  Our GWAS identified five novel susceptibility loci for CHB. These findings improve the understanding of CHB etiology and may provide new targets for prevention and treatment of this disease.
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.|Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.|Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China.|Center for Genetic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China.|Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC.
authors: De-Ke
authors: DK
authors: Jiang
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors: Xiao-Pin
authors: XP
authors: Ma
authors: James D. Watson Institute of Genome Sciences, College of life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors: Hongjie
authors: H
authors: Yu
authors: Department of Epidemiology, Second Military Medical University, Shanghai, China.
authors: Guangwen
authors: G
authors: Cao
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors: Dong-Lin
authors: DL
authors: Ding
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.|Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.|Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China.|Center for Genetic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China.
authors: Haitao
authors: H
authors: Chen
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors: Hui-Xing
authors: HX
authors: Huang
authors: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.
authors: Yu-Zhen
authors: YZ
authors: Gao
authors: 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, China.
authors: Xiao-Pan
authors: XP
authors: Wu
authors: Department of Pathology, Youjiang Medical College for Nationalities, Guangxi, China.
authors: Xi-Dai
authors: XD
authors: Long
authors: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Hongxing
authors: H
authors: Zhang
authors: Institute of Urology and Nephrology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, China.|Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, China.
authors: Youjie
authors: Y
authors: Zhang
authors: Institute of Urology and Nephrology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, China.|Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, China.
authors: Yong
authors: Y
authors: Gao
authors: Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, China.
authors: Tao-Yang
authors: TY
authors: Chen
authors: Luoyang Central Hospital, Affiliated to Zhengzhou University, Luoyang, China.
authors: Wei-Hua
authors: WH
authors: Ren
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.|Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.|Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China.|Center for Genetic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China.
authors: Pengyin
authors: P
authors: Zhang
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.|Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.|Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China.|Center for Genetic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China.
authors: Zhuqing
authors: Z
authors: Shi
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors: Wei
authors: W
authors: Jiang
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors: Bo
authors: B
authors: Wan
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors: Hexige
authors: H
authors: Saiyin
authors: Department of Epidemiology, Second Military Medical University, Shanghai, China.
authors: Jianhua
authors: J
authors: Yin
authors: Department of Pathology, Youjiang Medical College for Nationalities, Guangxi, China.
authors: Yuan-Feng
authors: YF
authors: Zhou
authors: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Yun
authors: Y
authors: Zhai
authors: Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, China.
authors: Pei-Xin
authors: PX
authors: Lu
authors: Department of Epidemiology, Second Military Medical University, Shanghai, China.
authors: Hongwei
authors: H
authors: Zhang
authors: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Xiaoli
authors: X
authors: Gu
authors: Institute of Urology and Nephrology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, China.|Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, China.
authors: Aihua
authors: A
authors: Tan
authors: Qidong Liver Cancer Institute, Qidong People's Hospital, Qidong, China.
authors: Jin-Bing
authors: JB
authors: Wang
authors: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, China.|State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, China.
authors: Xian-Bo
authors: XB
authors: Zuo
authors: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, China.|State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, China.
authors: Liang-Dan
authors: LD
authors: Sun
authors: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors: Jun O
authors: JO
authors: Liu
authors: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.|Division of Cancer Medicine, and the Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors: Qing
authors: Q
authors: Yi
authors: Institute of Urology and Nephrology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning, China.|Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, China.
authors: Zengnan
authors: Z
authors: Mo
authors: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Gangqiao
authors: G
authors: Zhou
authors: 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, China.
authors: Ying
authors: Y
authors: Liu
authors: Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC.
authors: Jielin
authors: J
authors: Sun
authors: Unit on Statistical Genomics, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
authors: Yin Yao
authors: YY
authors: Shugart
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.|Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.|Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC.|Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL.
authors: S Lilly
authors: SL
authors: Zheng
authors: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, China.|State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology, Hefei, China.
authors: Xue-Jun
authors: XJ
authors: Zhang
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.|Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.|Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China.|Center for Genetic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China.|Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL.
authors: Jianfeng
authors: J
authors: Xu
authors: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.|Institute of Biomedical Science, Fudan University, Shanghai, China.
authors: Long
authors: L
authors: Yu
mesh_terms: D019013:CD40 Antigens / Q000097:blood / Q000235:genetics*; D011415:Complement Factor B / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015236:HLA-C Antigens / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged
chemical_list: D019013:CD40 Antigens; D015236:HLA-C Antigens; D011415:Complement Factor B