ACPA-negative RA consists of two genetically distinct subsets based on RF positivity in Japanese

• Published in: PloS one Vol. 7; no. 7; p. e40067
• Main Authors: Terao, Chikashi, Ohmura, Koichiro, Ikari, Katsunori, Kochi, Yuta, Maruya, Etsuko, Katayama, Masaki, Yurugi, Kimiko, Shimada, Kota, Murasawa, Akira, Honjo, Shigeru, Takasugi, Kiyoshi, Matsuo, Keitaro, Tajima, Kazuo, Suzuki, Akari, Yamamoto, Kazuhiko, Momohara, Shigeki, Yamanaka, Hisashi, Yamada, Ryo, Saji, Hiroo, Matsuda, Fumihiko, Mimori, Tsuneyo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.07.2012; Public Library of Science (PLoS)
• Subjects: Alleles; Arthritis; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Asian Continental Ancestry Group - genetics; Autoantibodies - immunology; Autoimmune diseases; Biology; Citrulline; Comparative analysis; Drb1 protein; Epitopes; Ethnicity; Gene frequency; Genetic Predisposition to Disease; Genomes; Genotype; Genotyping; Haplotypes; Histocompatibility antigen HLA; HLA antigens; HLA-DRB1 Chains - genetics; HLA-DRB1 Chains - immunology; Hospitals; Humans; Immunology; Japan; Laboratories; Medicine; Patients; Population; Rheumatism; Rheumatoid arthritis; Rheumatoid factor; Rheumatoid Factor - immunology; Rheumatology; Transcription factors; University graduates; Womens health; Japan; United Kingdom > UK
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040067

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.