title: Identification of amino acids in antigen-binding site of class II HLA proteins independently associated with hepatitis B vaccine response.
abstract: Genetic factors in class II human leukocyte antigen (HLA) have been reported to be associated with inter-individual variation in hepatitis B virus (HBV) vaccine response. However, the mechanism underlying the associations remains elusive. In particular, the broad linkage disequilibrium in HLA region complicates the localization of the independent effects of genetic variants. Thus, the present study aimed to identify the most probable causal variations in class II HLA loci involved in the immune response to HBV vaccine.
  
  
  
  We performed a case-control study to assess whether HLA-DRB1, -DQB1, and -DPB1 4-digit alleles were associated with the response to primary HBV vaccination in 574 healthy Japanese students. To identify causative variants, we next assessed independently associated amino acid variants in these loci using conditional logistic regression analysis. Furthermore, to clarify the functional effects of these variants on HLA proteins, we performed computational structural studies.
  
  
  
  HLA-DRB1∗01:01, HLA-DRB1∗08:03, HLA-DQB1∗05:01, and HLA-DPB1∗04:02 were significantly associated with sufficient response, whereas HLA-DPB1∗05:01 was associated with poor response. We then identified amino acids independently associated with sufficient response, namely, leucine at position 26 of HLA-DRβ1 and glycine-glycine-proline-methionine at positions 84-87 of HLA-DPβ1. These amino acids were located in antigen-binding pocket 4 of HLA-DR and pocket 1 of HLA-DP, respectively, which are important structures for selective binding of antigenic peptides. In addition, the detected variations in HLA-DP protein were responsible for the differences in the electrostatic potentials of the pocket, which can explain in part the sufficient/poor vaccine responses.
  
  
  
  HLA-DRβ1 position 26 and HLA-DPβ1 positions 84-87 are independently associated with anti-HBs production against HBV vaccine. Our results suggest that HBsAg presentation through these HLA pocket structures plays an important role in the inter-individual variability of HBV vaccination.
authors.affiliation: Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address: sakai-ygt@umin.ac.jp.
authors.forename: Aiko
authors.initials: A
authors.lastname: Sakai
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address: enoguchi@md.tsukuba.ac.jp.
authors.forename: Emiko
authors.initials: E
authors.lastname: Noguchi
authors.affiliation: Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address: tksfksm@md.tsukuba.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Tagawa
authors.affiliation: Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwabuchi
authors.affiliation: Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kita
authors.affiliation: Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kakisaka
authors.affiliation: Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Miyasaka
authors.affiliation: Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takikawa
authors.affiliation: Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address: rsuma@md.tsukuba.ac.jp.
authors.forename: Ryo
authors.initials: R
authors.lastname: Sumazaki
mesh_terms: D000328:Adult; D000596:Amino Acids / Q000235:genetics* / Q000378:metabolism; D017951:Antigen Presentation / Q000235:genetics*; D044466:Asian People; D001665:Binding Sites; D016022:Case-Control Studies; D005260:Female; D064368:Healthy Volunteers; D006514:Hepatitis B Surface Antigens / Q000276:immunology*; D017325:Hepatitis B Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008958:Models, Molecular; D011487:Protein Conformation; D055815:Young Adult
chemical_list: D000596:Amino Acids; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D000949:Histocompatibility Antigens Class II
keywords: Antigen presentation; HLA-DP; HLA-DR; Hepatitis B surface antigen; Pocket; Responder