title: Fine mapping the MHC region identified four independent variants modifying susceptibility to chronic hepatitis B in Han Chinese.
abstract: Several genome-wide association studies (GWAS) have demonstrated the association between genetic variants in the major histocompatibility complex (MHC) region and chronic hepatitis B (CHB) virus infection, but it is still unknown about the disease-causing loci and potential mechanisms owing to the complicated linkage disequilibrium for this region. To systematically characterize the MHC variations in relation to the CHB infection, we fine mapped the MHC region on our existing GWAS data with SNP2HLA taken the Pan-Asian panel as reference and finally identified four independent associations. The HLA-DPβ1 amino acid positions 84-87, which drove the effect of reported single nucleotide polymorphisms rs9277535 and rs3077, showed the most significant association (OR = 0.65, P = 2.03 × 10(-8)). The Leu-15 of HLA-C, conferring the effect of rs3130542, increased the risk of CHB infection independently (OR = 1.61, P = 3.42 × 10(-7)). The HLA-DRβ1*13, in perfect LD with glutamic at site 71, and rs400488, an expression quantitative trait locus for HLA-J, were newly identified to be associated with CHB infection independently (OR = 1.84, P = 3.84 × 10(-9); OR = 0.28, P = 6.27 × 10(-7), respectively). HLA-DPβ1 positions 84-87 and HLA-DRβ1 position 71 implicated the P1 and P4 in the antigen-binding groove, whereas HLA-C position 15 affected the signal peptide. These four independent loci together can explain ∼ 6% of the phenotypic variance for CHB infection, accounting for 72.94% of that explained by known genetic variations. We fine mapped the MHC region and identified four loci that independently drove the chronic HBV infection. The results provided a deeper understanding of the GWAS signals and identified additional susceptibility loci which were missed in previous association studies.
authors.affiliation: Department of Epidemiology, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Epidemiology, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Juncheng
authors.initials: J
authors.lastname: Dai
authors.affiliation: Department of Epidemiology, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Epidemiology, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and.
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Epidemiology, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and.
authors.forename: Na
authors.initials: N
authors.lastname: Qin
authors.affiliation: Department of Epidemiology, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Epidemiology, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and.
authors.forename: Ci
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Infectious Diseases, Jiangsu Province Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Zhai
authors.affiliation: Eastern Hepatobiliary Surgery Hospital and.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Tumor Biobank, Nantong Tumor Hospital, Nantong, China.
authors.forename: Jibin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Tumor Biobank, Nantong Tumor Hospital, Nantong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Shengping
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore and.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Infectious Diseases, Jiangsu Province Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Infectious Diseases, Jiangsu Province Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Fengcai
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Epidemiology, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Epidemiology, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing 211166, China, zhibin_hu@njmu.edu.cn guangfujin@njmu.edu.cn EHPHWP@126.com.
authors.forename: Guangfu
authors.initials: G
authors.lastname: Jin
authors.affiliation: Eastern Hepatobiliary Surgery Hospital and National Innovation Alliance for Hepatitis & Liver Cancer, Second Military Medical University, Shanghai, China, zhibin_hu@njmu.edu.cn guangfujin@njmu.edu.cn EHPHWP@126.com.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Epidemiology, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing 211166, China, zhibin_hu@njmu.edu.cn guangfujin@njmu.edu.cn EHPHWP@126.com.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
mesh_terms: D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D004198:Disease Susceptibility; D005006:Ethnicity / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D015236:HLA-C Antigens / Q000235:genetics; D006239:Haplotypes; D019694:Hepatitis B, Chronic / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008285:Major Histocompatibility Complex / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D015236:HLA-C Antigens