ACPA-negative RA consists of two genetically distinct subsets based on RF positivity in Japanese.
HLA-DRB1, especially the shared epitope (SE), is strongly associated with rheumatoid arthritis (RA). However, recent studies have shown that SE is at most weakly associated with RA without anti-citrullinated peptide/protein antibody (ACPA). We have recently reported that ACPA-negative RA is associated with specific HLA-DRB1 alleles and diplotypes. Here, we attempted to detect genetically different subsets of ACPA-negative RA by classifying ACPA-negative RA patients into two groups based on their positivity for rheumatoid factor (RF). HLA-DRB1 genotyping data for totally 954 ACPA-negative RA patients and 2,008 healthy individuals in two independent sets were used. HLA-DRB1 allele and diplotype frequencies were compared among the ACPA-negative RF-positive RA patients, ACPA-negative RF-negative RA patients, and controls in each set. Combined results were also analyzed. A similar analysis was performed in 685 ACPA-positive RA patients classified according to their RF positivity. As a result, HLA-DRB1*04:05 and *09:01 showed strong associations with ACPA-negative RF-positive RA in the combined analysis (p = 8.8×10(-6) and 0.0011, OR: 1.57 (1.28-1.91) and 1.37 (1.13-1.65), respectively). We also found that HLA-DR14 and the HLA-DR8 homozygote were associated with ACPA-negative RF-negative RA (p = 0.00022 and 0.00013, OR: 1.52 (1.21-1.89) and 3.08 (1.68-5.64), respectively). These association tendencies were found in each set. On the contrary, we could not detect any significant differences between ACPA-positive RA subsets. As a conclusion, ACPA-negative RA includes two genetically distinct subsets according to RF positivity in Japan, which display different associations with HLA-DRB1. ACPA-negative RF-positive RA is strongly associated with HLA-DRB1*04:05 and *09:01. ACPA-negative RF-negative RA is associated with DR14 and the HLA-DR8 homozygote.
Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan. a0001101@kuhp.kyoto-u.ac.jp
Chikashi
C
Terao
Koichiro
K
Ohmura
Katsunori
K
Ikari
Yuta
Y
Kochi
Etsuko
E
Maruya
Masaki
M
Katayama
Kimiko
K
Yurugi
Kota
K
Shimada
Akira
A
Murasawa
Shigeru
S
Honjo
Kiyoshi
K
Takasugi
Keitaro
K
Matsuo
Kazuo
K
Tajima
Akari
A
Suzuki
Kazuhiko
K
Yamamoto
Shigeki
S
Momohara
Hisashi
H
Yamanaka
Ryo
R
Yamada
Hiroo
H
Saji
Fumihiko
F
Matsuda
Tsuneyo
T
Mimori
D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D044466:Asian People / Q000235:genetics*; D001323:Autoantibodies / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology; D006801:Humans; D007564:Japan; D012217:Rheumatoid Factor / Q000276:immunology*
D001323:Autoantibodies; D059811:HLA-DRB1 Chains; D012217:Rheumatoid Factor