PMID- 28043736 OWN - NLM STAT- MEDLINE DCOM- 20171215 LR - 20221207 IS - 1873-2518 (Electronic) IS - 0264-410X (Linking) VI - 35 IP - 4 DP - 2017 Jan 23 TI - Identification of amino acids in antigen-binding site of class II HLA proteins independently associated with hepatitis B vaccine response. PG - 703-710 LID - S0264-410X(16)30764-2 [pii] LID - 10.1016/j.vaccine.2016.08.068 [doi] AB - BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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-DRbeta1 and glycine-glycine-proline-methionine at positions 84-87 of HLA-DPbeta1. 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. CONCLUSION: HLA-DRbeta1 position 26 and HLA-DPbeta1 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. CI - Copyright (c) 2017 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Sakai, Aiko AU - Sakai A AD - Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address: sakai-ygt@umin.ac.jp. FAU - Noguchi, Emiko AU - Noguchi E AD - Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address: enoguchi@md.tsukuba.ac.jp. FAU - Fukushima, Takashi AU - Fukushima T AD - Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address: tksfksm@md.tsukuba.ac.jp. FAU - Tagawa, Manabu AU - Tagawa M AD - Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. FAU - Iwabuchi, Atsushi AU - Iwabuchi A AD - Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. FAU - Kita, Masaki AU - Kita M AD - Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan. FAU - Kakisaka, Keisuke AU - Kakisaka K AD - Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan. FAU - Miyasaka, Akio AU - Miyasaka A AD - Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan. FAU - Takikawa, Yasuhiro AU - Takikawa Y AD - Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan. FAU - Sumazaki, Ryo AU - Sumazaki R AD - Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address: rsuma@md.tsukuba.ac.jp. LA - eng PT - Journal Article DEP - 20161230 PL - Netherlands TA - Vaccine JT - Vaccine JID - 8406899 RN - 0 (Amino Acids) RN - 0 (Hepatitis B Surface Antigens) RN - 0 (Hepatitis B Vaccines) RN - 0 (Histocompatibility Antigens Class II) SB - IM MH - Adult MH - Amino Acids/*genetics/metabolism MH - Antigen Presentation/*genetics MH - Asian People MH - Binding Sites MH - Case-Control Studies MH - Female MH - Healthy Volunteers MH - Hepatitis B Surface Antigens/*immunology MH - Hepatitis B Vaccines/administration & dosage/*immunology MH - Histocompatibility Antigens Class II/chemistry/*genetics/metabolism MH - Humans MH - Male MH - Models, Molecular MH - Protein Conformation MH - Young Adult OTO - NOTNLM OT - Antigen presentation OT - HLA-DP OT - HLA-DR OT - Hepatitis B surface antigen OT - Pocket OT - Responder EDAT- 2017/01/04 06:00 MHDA- 2017/12/16 06:00 CRDT- 2017/01/04 06:00 PHST- 2016/04/19 00:00 [received] PHST- 2016/07/29 00:00 [revised] PHST- 2016/08/23 00:00 [accepted] PHST- 2017/01/04 06:00 [pubmed] PHST- 2017/12/16 06:00 [medline] PHST- 2017/01/04 06:00 [entrez] AID - S0264-410X(16)30764-2 [pii] AID - 10.1016/j.vaccine.2016.08.068 [doi] PST - ppublish SO - Vaccine. 2017 Jan 23;35(4):703-710. doi: 10.1016/j.vaccine.2016.08.068. Epub 2016 Dec 30.