Background 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) [2-3]. We have recently reported that ACPA-negative RA is associated with specific HLA-DRB1 alleles and diplotypes . 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.
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
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.