title: A large-scale association study identified multiple HLA-DRB1 alleles associated with ACPA-negative rheumatoid arthritis in Japanese subjects.
abstract: BACKGROUND
  HLA-DRB1 is associated with rheumatoid arthritis (RA). However, it has recently been suggested that HLA-DRB1 is only associated with patients with RA who have anticitrullinated peptide/protein antibodies (ACPA), which are specific to RA.
  
  
  OBJECTIVE
  To elucidate whether specific HLA-DR alleles are associated with ACPA-negative RA development.
  
  
  METHODS
  HLA-DRB1 typing was carried out in 368 Japanese ACPA-negative patients with RA and 1508 healthy volunteers as the first set, followed by HLA-DRB1 typing of 501 cases and 500 controls as the second set. The HLA-DRB1 allele frequency and diplotype frequency were compared in each group, and the results of the two studies were combined to detect HLA-DRB1 alleles or diplotypes associated with ACPA-negative RA.
  
  
  RESULTS
  HLA-DRB1*12:01 was identified as a novel susceptibility allele for ACPA-negative RA (p=0.000088, OR=1.72, 95% CI 1.31 to 2.26). HLA-DRB1*04:05 and *14:03 showed moderate associations with ACPA-negative RA (p=0.0063, OR=1.26, 95% CI 1.07 to 1.49 and p=0.0043, OR=1.81, 95% CI 1.20 to 2.73, respectively). The shared epitope was weakly associated with ACPA-negative RA, but no dosage effect was detected (p=0.016, OR=1.17, 95% CI 1.03 to 1.34). A combination of HLA-DRB1*12:01 and DRB1*09:01 showed a strong association with susceptibility to ACPA-negative RA (p=0.00013, OR=3.62, 95% CI 1.79 to 7.30). Homozygosity for HLA-DR8 was significantly associated with ACPA-negative RA (p=0.0070, OR=2.16, 95% CI 1.22 to 3.82). It was also found that HLA-DRB1*15:02 and *13:02 were protective against ACPA-negative RA (p=0.00010, OR=0.68, 95% CI 0.56 to 0.83 and p=0.00059, OR=0.66, 95% CI 0.52 to 0.84, respectively).
  
  
  CONCLUSIONS
  In this large-scale association study multiple alleles and diplotypes were found to be associated with susceptibility to, or protection against, ACPA-negative RA.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Terao
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ohmura
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kochi
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikari
authors.forename: Etsuko
authors.initials: E
authors.lastname: Maruya
authors.forename: Masaki
authors.initials: M
authors.lastname: Katayama
authors.forename: Kota
authors.initials: K
authors.lastname: Shimada
authors.forename: Akira
authors.initials: A
authors.lastname: Murasawa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Honjo
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takasugi
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tajima
authors.forename: Akari
authors.initials: A
authors.lastname: Suzuki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Shigeki
authors.initials: S
authors.lastname: Momohara
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.forename: Hiroo
authors.initials: H
authors.lastname: Saji
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D001323:Autoantibodies / Q000097:blood*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006650:Histocompatibility Testing / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide