title: Rare inborn errors associated with chronic hepatitis B virus infection.
abstract: Chronic hepatitis B (CHB) is a major global health issue. The role of rare genetic variants in CHB has not been elucidated. We aimed to identify rare allelic variants predisposing to CHB. We performed exome sequencing in 50 CHB patients who had no identifiable risk factors for CHB and 40 controls who were healthy and hepatitis B surface antibody-positive, but had never received hepatitis B vaccination. We selected six rare variant alleles and followed up their association with disease status by Sanger sequencing in a case-control study comprising 1,728 CHB patients and 1,636 healthy controls. The latter had either not been immunized with hepatitis B vaccine or had uncertain vaccination status. Our results showed that transmembrane protein 2 p.Ser1254Asn, interferon alpha 2 p.Ala120Thr, its regulator NLR family member X1 p.Arg707Cys, and complement component 2 p.Glu318Asp were associated with CHB, with P values of <1.0 × 10(-7) , 2.76 × 10(-5) , 5.08 × 10(-5) , 2.78 × 10(-4) and odds ratios (ORs) of 2.45, 4.08, 2.34, and 1.97, respectively. The combined P value was <2.0 × 10(-16) . As there has been no indication of immunological functions for the associated gene, transmembrane protein 2, we further studied its expression by immunohistochemistry, real-time polymerase chain reaction, and western blotting. Our results showed that it was strongly expressed by healthy hepatocytes, but its expression was reduced in liver tissues with CHB, hepatitis B viral (HBV) genome-containing HepG2.2.15 cells, as compared with healthy liver tissues and non-HBV genome-containing HepG2 cells (P = 0.022 and 0.0036, respectively).
  
  
  CONCLUSIONS
  We identified four missense mutations associated with CHB, our results providing evidence for rare inborn genetic defects that contribute to increased host susceptibility to CHB.
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.forename: Weijun
authors.initials: W
authors.lastname: Huang
authors.forename: Qibin
authors.initials: Q
authors.lastname: Li
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Pei
authors.forename: Ping
authors.initials: P
authors.lastname: Yuan
authors.forename: Lingyan
authors.initials: L
authors.lastname: Zheng
authors.forename: Yongling
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jia
authors.initials: J
authors.lastname: Deng
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhong
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Hongke
authors.initials: H
authors.lastname: Ding
authors.forename: Wei
authors.initials: W
authors.lastname: Fang
authors.forename: Ru
authors.initials: R
authors.lastname: Li
authors.forename: Qijun
authors.initials: Q
authors.lastname: Liao
authors.forename: Chaoshuang
authors.initials: C
authors.lastname: Lin
authors.forename: Weiping
authors.initials: W
authors.lastname: Deng
authors.forename: Huijun
authors.initials: H
authors.lastname: Yan
authors.forename: Jinghui
authors.initials: J
authors.lastname: Hou
authors.forename: Qiuliang
authors.initials: Q
authors.lastname: Wu
authors.forename: Tingting
authors.initials: T
authors.lastname: Xu
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Longbo
authors.initials: L
authors.lastname: Hu
authors.forename: Tao
authors.initials: T
authors.lastname: Peng
authors.forename: Suqing
authors.initials: S
authors.lastname: Chen
authors.forename: Kar N
authors.initials: KN
authors.lastname: Lai
authors.forename: Man-Fung
authors.initials: MF
authors.lastname: Yuen
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Mala K
authors.initials: MK
authors.lastname: Maini
authors.forename: Caixia
authors.initials: C
authors.lastname: Li
authors.forename: Miaoxin
authors.initials: M
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Zhang
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Sham
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Gao
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D003175:Complement C2 / Q000737:chemistry / Q000235:genetics; D059472:Exome; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D056945:Hep G2 Cells; D006514:Hepatitis B Surface Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000737:chemistry / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics; D008961:Models, Structural; D020125:Mutation, Missense; D016017:Odds Ratio; D017422:Sequence Analysis, DNA
chemical_list: C408224:CEMIP2 protein, human; D003175:Complement C2; D006514:Hepatitis B Surface Antigens; D016898:Interferon-alpha; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C527006:NLRX1 protein, human