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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.

Objectives:Interferon regulatory factor 5 (IRF5) is a member of the IRF family of transcription factors, which regulate the production of proinflammatory cytokines. Polymorphisms in the IRF5 gene have been associated with susceptibility to systemic lupus erythaematosus (SLE) in Caucasian and Asian populations, but their involvement in other autoimmune diseases is still uncertain. Here, we assessed the genetic role of IRF5 in susceptibility to rheumatoid arthritis (RA) in Japanese subjects.Methods:We selected 13 single nucleotide polymorphisms (SNPs) and a CGGGG insertion–deletion polymorphism in the IRF5 gene. We performed 2 sets of case–control comparisons using Japanese subjects (first set: 830 patients with RA and 658 controls; second set: 1112 patients with RA and 940 controls), and then performed a stratified analysis using human leukocyte antigen (HLA)-DRB1 shared epitope (SE) status. We genotyped the SNPs using TaqMan assays.Results:A significant association of the rs729302 A allele with RA susceptibility was found in both sets (odds ratio (OR) 1.22, 95% CI 1.09 to 1.35, pConclusions:These findings indicate that the promoter polymorphism of IRF5 is a genetic factor conferring predisposition to RA, and that it contributes considerably to disease pathogenesis in patients that were SE negative.

ObjectiveTo elucidate the differential role of peptidyl arginine deiminase 4 (PADI4) polymorphism in rheumatoid arthritis (RA) between Asian and European populations, possible gene–environmental interactions among the PADI4 polymorphism, sex and smoking status were analysed.MethodsThree independent sets of case–control samples were genotyped for single-nucleotide polymorphisms in PADI4; Japanese samples (first set, 1019 RA patients, 907 controls; second set, 999 RA patients, 1128 controls) using TaqMan assays and Dutch samples (635 RA patients, 391 controls) using Sequenom MassARRAY platform. The association of PADI4 with RA susceptibility was evaluated by smoking status and sex in contingency tables and logistic regression models.ResultsIn the first set of Japanese samples, PADI4 polymorphism (rs1748033) showed a greater risk in men (ORallele 1.39; 95% CI 1.10 to 1.76; ptrend=0.0054) than in women and in ever-smokers (ORallele 1.25; 95% CI 1.02 to 1.53; ptrend=0.032) than in never-smokers. Moreover, the highest risk was seen in male ever-smokers (ORallele 1.46; 95% CI 1.12 to 1.90; ptrend=0.0047). Similar trends were observed in the second set of Japanese samples as well as in Dutch samples.ConclusionPADI4 polymorphism highly predisposes male smokers to RA, and the genetic heterogeneity observed between Asian and European populations may be partly explained by differences in smoking prevalence among men.

Background Susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by the development of genome-wide association studies (GWAS). However, little is known about the genetic background of ACPA-negative RA. Objectives We intended to clarify genetic background of ACPA-negative RA and compare susceptibility genes between ACPA-negative and -positive RA. Methods We performed a meta-analysis of GWAS comprising 670 ACPA-negative RA and 16,891 controls for 1,948,138 markers, followed by a replication study of the top 35 SNPs using 916 cases and 3,764 controls. Inverse-variance method was applied to assess overall effects. To assess overlap of susceptibility genes between ACPA-positive and -negative RA, odds ratios (ORs) of the 21 susceptibility markers to RA in Japanese were compared between the two subsets. In addition, SNPs were stratified by the p-values in GWAS meta-analysis for either ACPA-positive RA or ACPA-negative RA to address the question whether weakly-associated genes were also shared. The correlations between ACPA-positive RA and the subpopulations of ACPA-negative RA (rheumatoid factor (RF)-positive and RF-negative subsets) were also addressed. Results Rs6904716 in LEMD2 of the HLA locus showed a borderline association with ACPA-negative RA (overall p=5.7x10–8), followed by rs6986423 in CSMD1 (p=2.4x10–6) and rs17727339 in FCRL3 (p=1.4x10–5). ACPA-negative RA showed significant correlations of ORs with ACPA-positive RA for the 21 susceptibility SNPs and non-HLA SNPs with p-values far from significance. These significant correlations with ACPA-positive RA were true for ACPA-negative RF-positive and ACPA-negative RF-negative RA. On the contrary, positive correlations were not observed between the ACPA-negative two subpopulations. ![Figure][1] Conclusions Many of the susceptibility genes were shared between ACPA-positive and -negative RA. Acknowledgements We'd like to thank all doctors who helped us to collect DNA samples from patients with ACPA-negative RA. We'd like to thank especially Drs. Takao Fujii, Hiromu Ito, Motomu Hashimoto and Moritoshi Furu for their effort for sample accumulation. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.3219 [1]: pending:yes

Anti-cyclic citrullinated peptide (anti-CCP) antibody is a highly specific biomarker for rheumatoid arthritis (RA), and is recognised as a predictor of the development of RA.1 2 It has been demonstrated that some HLA-DRB1 alleles, such as shared epitope (SE) alleles, significantly contribute to the positivity of anti-CCP antibody and the susceptibility of anti-CCP antibody-positive RA.3 4 However, the quantitative effect of HLA-DRB1 alleles on anti-CCP antibody levels in RA patients is controversial.3 5 6 Therefore, we carried out a large-scale study to study the quantitative effects of HLA-DRB1 alleles on anti-CCP antibody levels in Japanese patients with RA. A total of 2384 Japanese patients with RA was recruited through several medical institutes of Japan under the support of the BioBank Japan Project7 (age 61.5±11.8 years (mean±SD), 81.2% were women). All patients fulfilled the American College of Rheumatology revised criteria for RA, and provided written informed consent. Serum anti-CCP antibody levels were assayed using the second-generation anti-CCP ELISA kit (DIASTAT Anti-CCP; MBL, Nagoya, Japan) with …

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

Background Systemic lupus erythematosus (SLE) is an autoimmune disease that displays clinical heterogeneity. The detailed distributions of its symptoms and clinical markers are unknown. Objectives We performed a nation-wide study to determine the distributions of the signs and clinical markers of SLE and identify any patterns in their distributions to allow patient subclassification. Methods We obtained a total of 256,999 patient-year records describing the disease statuses of SLE patients, including the diagnostic symptoms that they possessed, from the Japanese national registry system from 2003 to 2010. Of these, 14,779 involved patients who had been diagnosed with SLE within the last year, and 242,220 involved patients who were being followed-up. In addition to calculating basic descriptive statistics, we performed multiple logistic regression analyses to analyze the effects of sex, age, and disease duration on the frequencies of symptoms in the first year and follow-up years. The distributions of SLE complications were also analyzed. The patients and diagnostic symptoms were clustered using the Ward method. Results The age-standardized incidence and prevalence of SLE were estimated to be 1.94 and 35.21 per 100,000 people, respectively, and the female:male ratio was 8.23. The female patients were significantly younger at onset than the male patients(p -10 ). The frequency of a relevant family history was associated with a younger age-at-onset of SLE(p=8.0x10 -5 ). Renal involvement and discoid eczema were more frequent in males(p -10 ), whereas arthritis, photosensitivity, and cytopenia were more common in females(p -10 ). Autoantibody production and malar rash were positively associated with young age(p -10 ), and serositis and arthritis were associated with old age(p -10 ). Photosensitivity was positively associated with a long disease duration(p -10 ), and autoantibody production, serositis, and cytopenia were associated with a short disease duration(p -10 ). The SLE patients were clustered into ten and eight sub-groups in the first and follow-up years, respectively. Diagnostic symptoms of SLE were clustered into two subgroups in both first and follow-up years with difference of finer cluster divisions. The first group included hematoserological abnormalities and the second group included organ-specific abnormalities. The age-standardized risks of cerebral and myocardial infarction were 3.79 (2.87-4.72) and 2.44 (2.16-2.72) times higher in the SLE patients compared with the general population, respectively, and the increase in risk was positively associated with the number of positive tests for APS-related markers (p Conclusions Along with the well-known female predominance of SLE, we identified differences in its clinical features between the sexes and patients with different onset ages. Also our large-scale study indicated that subgroups of SLE patients and the diagnostic symptoms of SLE exist. Disclosure of Interest None Declared