title: An association between amino acid position 74 of HLA-DRB1 and anti-citrullinated protein antibody levels in Japanese patients with anti-citrullinated protein antibody-positive rheumatoid arthritis.
abstract: OBJECTIVE
  Anti-citrullinated protein antibodies (ACPAs) are highly specific to rheumatoid arthritis (RA), and strong associations between HLA-DRB1 alleles and ACPA levels have been detected in RA patients. We undertook this study to elucidate the associations between particular amino acid positions in HLA-DRB1 and ACPA levels in patients with RA.
  
  
  METHODS
  We analyzed ACPA data on a total of 4,371 Japanese ACPA-positive RA patients in whom HLA-DRB1 allele genotyping had been performed. Generalized linear regression analysis and omnibus testing were carried out to determine associations of HLA-DRB1 alleles, amino acid residues, or amino acid positions with levels of ACPA.
  
  
  RESULTS
  HLA-DRB1*09:01 and HLA-DR15 were confirmed to be associated with ACPA levels. HLA-DRB1*08:03 and DRB1*14:06 were associated with reduced and increased ACPA levels, respectively. We detected a strong association between ACPA levels and amino acid position 74 (P = 1.9 × 10(-51) ). The association was mainly conferred by alanine residue (P = 4.5 × 10(-51) ). After adjustment for position 74, amino acid positions 60 and 57 were found to be associated with ACPA levels. Amino acid positions 74 and 57 had previously been reported to be associated with susceptibility to ACPA-positive RA in Asians. Combinations of the amino acid residues at position 74 and position 60 or 57 could induce improvement in Akaike's information criterion comparable to that induced by the 5 significant HLA-DRB1 alleles (HLA-DRB1*08:03, DRB1*09:01, DRB1*14:06, DRB1*15:01, and DRB1*15:02).
  
  
  CONCLUSIONS
  Amino acid position 74 in HLA-DRB1 is strongly associated with ACPA levels in ACPA-positive RA, as well as with RA susceptibility. The mechanisms of ACPA production and susceptibility to ACPA-positive RA seem to partly overlap.
authors.affiliation: Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Terao
authors.affiliation: Center for Genomic Medicine, RIKEN, Yokohama, Japan.
authors.forename: Akari
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikari
authors.affiliation: Center for Genomic Medicine, RIKEN, Yokohama, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kochi
authors.affiliation: Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ohmura
authors.affiliation: Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Katayama
authors.affiliation: Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Nakabo
authors.affiliation: Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Iwamoto
authors.affiliation: Kyoto University Hospital, Kyoto, Japan.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Yurugi
authors.affiliation: Kyoto University Hospital, Kyoto, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Kyoto University Hospital, Kyoto, Japan.
authors.forename: Taira
authors.initials: T
authors.lastname: Maekawa
authors.affiliation: Dohgo Spa Hospital, Matsuyama, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takasugi
authors.affiliation: Center for Genomic Medicine, RIKEN, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: HLA Laboratory, Kyoto, Japan.
authors.forename: Hiroh
authors.initials: H
authors.lastname: Saji
authors.affiliation: Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Taniguchi
authors.affiliation: Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Momohara
authors.affiliation: University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamanaka
authors.affiliation: Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
authors.affiliation: Kyoto University Graduate School of Medicine and INSERM U852, Kyoto, Japan, and CREST Program, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D001323:Autoantibodies / Q000276:immunology*; D005260:Female; D005838:Genotype; D059810:HLA-DR Serological Subtypes / Q000235:genetics / Q000378:metabolism; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D059810:HLA-DR Serological Subtypes; C106559:HLA-DR15 antigen; D059811:HLA-DRB1 Chains; C487381:HLA-DRB1*09:01 antigen; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide