SAT0002 ACPA-negative rheumatoid arthritis consists of two genetically distinct subsets based on RF positivity

Background HLA-DRB1, especially the shared epitope (SE), is strongly associated with rheumatoid arthritis (RA) [1]. However, recent studies have shown that SE is at most weakly associated with RA without anti-citrullinated peptide/protein antibody (ACPA) [2-3]. We have recently reported that ACPA-negative RA is associated with specific HLA-DRB1 alleles and diplotypes [4]. While HLA-DRB1*04:05 and *09:01 showed strong associations with ACPA-positive RA, they showed just potential associations with ACPA-negative RA. Objectives 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). Methods HLA-DRB1 genotyping data for totally 866 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 667 ACPA-positive RA patients classified according to their RF positivity. Results HLA-DRB1*09:01 and *04:05 showed strong associations only with ACPA-negative RF-positive RA in the combined analysis (p=0.00038 and 0.00010, OR: 1.42 (1.17-1.72) and 1.50 (1.22-1.85), respectively). We also found that HLA-DR14 and the HLA-DR8 homozygote were associated only with ACPA-negative RF-negative RA (p=0.00039 and 6.2×10 -5 , OR: 1.52 (1.20-1.91) and 3.28 (1.78-6.07), respectively). These association tendencies were found in each set. Other alleles and diplotypes shown in our previous study showed associations with both ACPA-negative subsets. While we found clear difference of HLA-DRB1 associations in two ACPA-negative subsets, we could not detect any significant differences between ACPA-positive RA subsets. Conclusions ACPA-negative RA includes two genetically distinct subsets according to RF positivity, which display different associations with HLA-DRB1. ACPA-negative RF-positive RA is strongly associated with HLA-DRB1*04:05 and *09:01, indicating some genetic similarities between ACPA-positive RA and ACPA-negative RF-positive RA. ACPA-negative RF-negative RA is associated with DR14 and the HLA-DR8 homozygote. References Gregersen PK, Silver J, Winchester RJ. Arthritis Rheum. 1987;30(11):1205-13. van der Woude D, Lie BA, Lundstrom E, Balsa A, Feitsma AL, Houwing-Duistermaat JJ, et al. Arthritis Rheum. 2010;62(5):1236-45. Ohmura K, Terao C, Maruya E, Katayama M, Matoba K, Shimada K, et al. Rheumatology (Oxford). 2010;49(12):2298-304. Terao C, Ohmura K, Kochi Y, Ikari K, Maruya E, Katayama M, et al. Ann Rheum Dis. 2011;70(12):1234-9. Disclosure of Interest None Declared