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Annals of the rheumatic diseases 03/2013; · 8.11 Impact Factor
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Kenichi Shimane,
Yuta Kochi,
Akari Suzuki,
Yukinori Okada,
Tomonori Ishii,
Tetsuya Horita,
Kazuyoshi Saito,
Akiko Okamoto,
Norihiro Nishimoto,
Keiko Myouzen,
Michiaki Kubo,
Michito Hirakata,
Takayuki Sumida,
Yoshinari Takasaki,
Ryo Yamada,
Yusuke Nakamura,
Naoyuki Kamatani, Kazuhiko Yamamoto
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ABSTRACT: Objective. To re-evaluate the roles of HLA-DRB1 alleles in susceptibility to SLE and RA and their effects on autoantibody status in large-scale Japanese cohorts.Methods. A total of 656 SLE, 2410 RA and 911 control subjects, who were all Japanese, were genotyped for HLA-DRB1 alleles using sequence-specific oligonucleotide probes. The association of alleles with disease susceptibility was tested by logistic regression analysis and by the relative predispositional effect method. The association with autoantibody status was examined by the standard χ(2) test.Results. HLA-DRB1*15:01, *09:01, *08:02 and *04:01 were significantly associated with SLE susceptibility, while shared epitope (SE) alleles and DRB1*09:01 were associated with RA susceptibility. The compound heterozygote of DRB1*09:01/*15:01 conferred an increased risk for SLE compared with the homozygotes for DRB1*09:01 and *15:01 and was associated with earlier onset of disease, whereas the compound effect of DRB1-SE/*09:01 was not clear in RA. DRB1*09:01 was significantly associated with the appearance of anti-Sm antibody in SLE as well as ACPA in RA, while protectively associated with anti-dsDNA antibody in SLE. No significant interaction was observed between DRB1*09:01 and smoking status for the appearance of ACPA, unlike that observed in SE alleles in RA.Conclusion. We identified HLA-DRB1 alleles associated with SLE and RA in a Japanese population and demonstrated a shared susceptibility of DRB1*09:01 between the diseases as well as its effect on autoantibody production.
Rheumatology (Oxford, England) 02/2013; · 4.24 Impact Factor
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ABSTRACT: Interleukin-27 (IL-27) suppresses immune responses through inhibition of the development of IL-17 producing T-helper (Th) 17 cells and induction of IL-10 production. We previously showed that forced expression of early growth response gene 2 (Egr-2), a transcription factor required for T-cell anergy induction, induces IL-10 and lymphocyte activation gene 3 (LAG-3) expression and confers regulatory activity on CD4(+) T cells in vivo. Here we evaluated the role of Egr-2 in IL-27-induced IL-10 production. Among various IL-10-inducing factors, only IL-27 induced high levels of Egr-2 and LAG-3 expression. Intriguingly, IL-27 failed to induce IL-10 in Egr-2-deficient T cells. IL-27-mediated induction of Prdm1 that codes Blimp-1, a transcriptional regulator important for IL-10 production in CD4(+) T cells, was also impaired in the absence of Egr-2. Although IL-27-mediated IL-10 induction was dependent on both STAT1 and STAT3, only STAT3 was required for IL-27-mediated Egr-2 induction. These results suggest that IL-27 signal transduction through Egr-2 and Blimp-1 plays an important role in IL-10 production. Furthermore, Egr-2-deficient CD4(+) T cells showed dysregulated production of IFN-γ and IL-17 in response to IL-27 stimulation. Therefore, Egr-2 may play key roles in controlling the balance between regulatory and effector cytokines.
European Journal of Immunology 01/2013; · 5.10 Impact Factor
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ABSTRACT: IL-10 is an anti-inflammatory cytokine with an important role in preventing inflammatory and autoimmune responses. IL-10 is also important for suppressive function of inducible regulatory T (iTreg) cells, several types of which were reported in succession. Type1 regulatory T (Tr1) cell is a representative of IL-10-prroducing regulatory T cells. Although specific surface markers or origin of Tr1 cells have not fully been clarified yet, IL-27 was recently reported to induce IL-10 production in T cells and be an inducer of Tr1 cells. We previously reported that CD4CD25lymphocyte activation gene (LAG-3) Treg (LAG3 Treg) is one of the peripherally inducible Tregs and functions as an immune-regulator through IL-10 production. We found that the expression level of Egr-2, a transcription factor required for T cell anergy induction, is elevated in LAG3 Treg and that forced expression of Egr-2 induces LAG-3 expression and IL-10 production. Egr-2 has been suggested to be a key player of regulatory function in LAG3 Treg. In this study, we review Tr1 cells and the mechanism of IL-10 induction by IL-27 in T cells. Also, we introduce LAG3 Treg and discuss the therapeutic potential of these regulatory T cells.
Japanese Journal of Clinical Immunology 01/2013; 36(1):40-6.
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ABSTRACT: OBJECTIVES: A multicenter, randomized, double-blind, placebo-controlled study of the oral calcineurin inhibitor tacrolimus was performed in patients with early rheumatoid arthritis who had responded poorly to disease-modifying antirheumatic drugs (DMARDs), and factors related to suppression of joint destruction were investigated. METHODS: The change in the total Sharp score (∆TSS) was assessed by univariate analysis in patients with X-ray films to identify the main determinant of a ∆TSS of <0.5 in week 52. Patients with this factor were then investigated further. RESULTS: Univariate analysis showed that a baseline C-reactive protein (CRP) level of <1.5 mg/dL was the major determinant of ∆TSS <0.5 at week 52 in the tacrolimus group. Detailed analysis of patients with a baseline CRP of <1.5 mg/dL revealed no significant differences in background factors between the two groups. In week 52, ∆TSS was significantly smaller in the tacrolimus group than in the placebo group (2.67 ± 5.40 vs. 8.05 ± 10.32, respectively, p = 0.017). Both groups had a similar incidence of adverse reactions. CONCLUSIONS: Adding tacrolimus to DMARDs significantly suppressed disease activity and joint destruction in patients with early rheumatoid arthritis, a disease duration ≤3 years, a CRP <1.5 mg/dL, and a poor response to oral DMARDs.
Modern Rheumatology 12/2012; · 1.58 Impact Factor
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ABSTRACT: Dysregulated autoantibody production is responsible for the severe organ damage that occurs in systemic autoimmune diseases. Immune complexes play important roles in the pathogenesis of these diseases as they initiate and maintain the inflammatory cascade, which leads to tissue destruction. Conventional therapy for autoimmune diseases suppresses immunological accelerator in the absence of knowledge of the immunological brake. Application of a physiological regulatory system could be a rational strategy to treat autoimmune diseases. Accumulating evidence has suggested that specialised subsets of B cells and T cells could control autoantibody production. A significant decrease and impaired function of regulatory B cells (Breg) was recently reported in patients with systemic lupus erythematosus and a mice model of lupus. In T cells, follicular regulatory T cells and Qa-1 restricted CD8 regulatory T cells (Treg) were identified as the populations that control follicular T helper cell-mediated antibody production. Moreover, other Treg populations might also be involved in the control of autoantibody production. Elucidating the roles of Breg and Treg in the control of antibody production might lead to the development of a new therapeutic approach to antibody-mediated autoimmune disease.
Annals of the rheumatic diseases 12/2012; · 8.11 Impact Factor
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Chikashi Terao,
Koichiro Ohmura,
Yasushi Kawaguchi,
Tetsuya Nishimoto,
Aya Kawasaki,
Kazuhiko Takehara,
Hiroshi Furukawa,
Yuta Kochi,
Yuko Ota,
Katsunori Ikari,
Shinichi Sato,
Shigeto Tohma,
Ryo Yamada, Kazuhiko Yamamoto,
Michiaki Kubo,
Hisashi Yamanaka,
Masataka Kuwana,
Naoyuki Tsuchiya,
Fumihiko Matsuda,
Tsuneyo Mimori
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ABSTRACT: BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease for which multiple susceptibility genes have been reported. Genome-wide association studies have shown that large numbers of susceptibility genes are shared among autoimmune diseases. Recently, we reported nine novel susceptibility genes for Japanese rheumatoid arthritis (RA). OBJECTIVE: To elucidate whether the 18 genes that displayed associations or suggestive associations for Japanese RA in our previous study are associated with SSc in Japanese. METHOD: We performed an association study involving 415 SSc patients and 16,891 controls, followed by a replication study, which involved 315 cases and 21,054 controls. The 18 markers were analyzed for their associations with SSc in the first study, and five markers were further analyzed in the replication study. The inverse-variance method was used to evaluate the associations of these markers with SSc in a combined study. RESULTS: Rs2841277 in the PLD4 gene displayed a significant association with SSc in Japanese patients (p=0.00017). We detected that rs2841280 in exon2 of PLD4 is in strong linkage disequilibrium with rs2841277 and introduces amino acid alteration. We also found associations between SSc and rs6932056 in TNFAIP3 and rs2280381 in IRF8 (p=0.0000095 and 0.0030), both of which displayed associations with SSc in a European population. CONCLUSIONS: We determined PLD4, phospholipase D4, as a novel susceptibility gene for SSc in Japanese, confirming the involvement of PLD4 in autoimmunity. Associations between SSc and TNFAIP3 or IRF8 were also detected in our Japanese population. SSc and RA seem to share relatively large proportions of their genetic backgrounds. © 2012 American College of Rheumatology.
Arthritis & Rheumatism 11/2012; · 7.87 Impact Factor
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ABSTRACT: A 75-year-old woman was admitted to our department because of backache and multiple joint pain. Serum C-reactive protein (CRP) level was 6.8 mg/dL, and serum rheumatoid factor and anti-citrullinated peptide antibody were negative. Magnetic resonance imaging (MRI) showed bone edema and synovitis of the sacroiliac joints. (18)Fluorodeoxyglucose-positron emission tomography ((18)FDG-PET) showed increased uptakes in the bilateral elbow, shoulder, sternoclavicular, hip, and sacroiliac joints. In addition, increased uptakes were also observed in the bilateral cervical and subclavian arteries, and the thoracic aorta. Moreover, inflammation of the vascular walls and an aneurism in the right subclavian artery were observed on MRI. The patient's HLA type was HLA-B48 and B60. According to the Assessment of Spondyloarthritis (ASAS) classification criteria, peripheral spondyloarthropathy (SpA) was also diagnosed. Although the diagnostic criteria of Takayasu aortitis or giant cell aortitis were not fulfilled, we thought that active aortitis was also involved, and high-dose prednisolone was started. The patient's symptoms were diminished immediately, and CRP levels returned to normal. Although the etiology of the aortitis was not certain, this is the first report of late-onset peripheral SpA with aortitis, diagnosed by (18)FDG-PET and MRI. We recommended that it is important to evaluate the aortic involvement in late-onset SpA patients, when elevated systemic inflammation is observed.
Modern Rheumatology 09/2012; · 1.58 Impact Factor
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Tsutomu Takeuchi,
Masayoshi Harigai,
Yoshiya Tanaka,
Hisashi Yamanaka,
Naoki Ishiguro, Kazuhiko Yamamoto,
Nobuyuki Miyasaka,
Takao Koike,
Minoru Kanazawa,
Takuya Oba,
Toru Yoshinari,
Daniel Baker
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ABSTRACT: OBJECTIVE: To evaluate the efficacy and safety of golimumab 50 and 100 mg monotherapy in Japanese patients with active rheumatoid arthritis (RA) despite treatment with disease-modifying antirheumatic drugs (DMARDs). METHODS: A total of 316 patients were randomised to receive subcutaneous injections every 4 weeks of placebo (group 1), golimumab 50 mg (group 2) or golimumab 100 mg (group 3); group 1 crossed over to golimumab 50 mg at week 16. The primary end point was the proportion of patients achieving ≥20% improvement in the American College of Rheumatology criteria (ACR20) at week 14. ACR50 and ACR70 response rates were also measured. Adverse events (AEs) were monitored throughout the study. RESULTS: Demographics were similar across groups; the mean age was 52 years and 81.8% of patients (252/308) were female. Week 14 ACR20 response rates were significantly greater in groups 2 (51/101 (50.5%)) and 3 (60/102 (58.8%)) than in group 1 (20/105 (19.0%); p<0.0001 for both), as were ACR50 and ACR70 response rates. After placebo crossover at week 16, week 24 ACR response rates were similar in groups 1 and 2. Through week 16, 63.8% of patients in group 1, 62.4% in group 2 and 60.8% in group 3 had AEs and 1.9%, 1.0% and 2.0% had serious AEs. After week 16, one malignancy was reported (breast cancer, group 3). Infections were the most common AEs. No deaths or cases of tuberculosis were reported through week 24. CONCLUSIONS: Golimumab monotherapy (50 and 100 mg) was effective in reducing the signs and symptoms of RA in Japanese patients with active disease despite DMARD treatment.
Annals of the rheumatic diseases 09/2012; · 8.11 Impact Factor
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Keiko Myouzen,
Yuta Kochi,
Yukinori Okada,
Chikashi Terao,
Akari Suzuki,
Katsunori Ikari,
Tatsuhiko Tsunoda,
Atsushi Takahashi,
Michiaki Kubo,
Atsuo Taniguchi,
Fumihiko Matsuda,
Koichiro Ohmura,
Shigeki Momohara,
Tsuneyo Mimori,
Hisashi Yamanaka,
Naoyuki Kamatani,
Ryo Yamada,
Yusuke Nakamura, Kazuhiko Yamamoto
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ABSTRACT: Rheumatoid arthritis is an autoimmune disease with a complex etiology, leading to inflammation of synovial tissue and joint destruction. Through a genome-wide association study (GWAS) and two replication studies in the Japanese population (7,907 cases and 35,362 controls), we identified two gene loci associated with rheumatoid arthritis susceptibility (NFKBIE at 6p21.1, rs2233434, odds ratio (OR) = 1.20, P = 1.3×10(-15); RTKN2 at 10q21.2, rs3125734, OR = 1.20, P = 4.6×10(-9)). In addition to two functional non-synonymous SNPs in NFKBIE, we identified candidate causal SNPs with regulatory potential in NFKBIE and RTKN2 gene regions by integrating in silico analysis using public genome databases and subsequent in vitro analysis. Both of these genes are known to regulate the NF-κB pathway, and the risk alleles of the genes were implicated in the enhancement of NF-κB activity in our analyses. These results suggest that the NF-κB pathway plays a role in pathogenesis and would be a rational target for treatment of rheumatoid arthritis.
PLoS Genetics 09/2012; 8(9):e1002949. · 8.69 Impact Factor
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ABSTRACT: A 28-year-old rheumatoid arthritis woman treated with adalimumab was admitted with fever, cough, and right chest pain. X-ray showed right pleural effusion. By medical thoracoscopy, diffuse white nodules were observed, and biopsy specimen demonstrated epithelioid cell granulomas with necrosis and auramine-stained organisms, which suggested a diagnosis of tuberculous pleurisy. Medical thoracoscopy can be a potent diagnostic method when tuberculous pleurisy is suspected. Notably, despite latent tuberculosis treatment, active tuberculosis was not prevented.
Modern Rheumatology 08/2012; · 1.58 Impact Factor
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ABSTRACT: OBJECTIVES: To investigate the efficacy and safety of iguratimod (T-614) in Japanese patients with active rheumatoid arthritis who had inadequate response to stable background methotrexate (MTX) alone. METHODS: In this multicenter, double-blind, controlled trial, a total of 253 patients were randomized at 2:1 ratio to either the iguratimod group or the placebo group. Iguratimod was orally administered at dosages of 25 mg/day for the first 4 weeks (25 mg once daily) and 50 mg/day for the subsequent 20 weeks (25 mg twice daily). MTX at dosage of 6 or 8 mg/week was administered to patients in both groups. RESULTS: The rate of 20 % improvement in American College of Rheumatology criteria (ACR20) at week 24 was 69.5 % in the iguratimod group compared with 30.7 % in the placebo group (P < 0.001). Significant improvements in the ACR50, ACR70, Health Assessment Questionnaire Disability Index, Disease Activity Score 28 <3.2, and rheumatoid factor were also observed. The most commonly reported adverse events (AEs) were blood iron decrease, nasopharyngitis, and lymphocyte decrease. These AEs were mild or moderate in severity. No deaths occurred. CONCLUSION: The study results suggest that iguratimod in combination with MTX was efficacious and had a manageable safety profile.
Modern Rheumatology 07/2012; · 1.58 Impact Factor
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ABSTRACT: To assess the long-term safety and efficacy of tacrolimus (TAC) used in combination with oral methotrexate (MTX) in patients with rheumatoid arthritis (RA) whose disease remains active despite treatment with MTX alone. The clinical courses of 24 RA patients who received TAC added to MTX from a single center were analyzed retrospectively. The disease activity was evaluated by the DAS28-ESR(3) every 12 months after the addition of TAC, and side effects were evaluated for 3 years. At 3 years after starting the treatment, TAC was still being used by 19 patients (79 %). The causes of discontinuation were an inadequate response (3 cases), oral ulcers and elevation of creatinine (1 case), and worsening of interstitial pneumonia (1 case). No death was registered. The DAS28-ESR(3) was decreased from 4.81 to 3.41 after 3 years of treatment. The doses of prednisolone were decreased from 5.1 mg/day to 3.2 mg/day after 3 years. In patients whose active RA persists despite treatment with MTX, TAC in combination with MTX is safe and well tolerated and provided clinical benefit for a long time in this single-center retrospective study. Further studies are required to confirm the safety and efficacy of this combination therapy.
Rheumatology International 07/2012; · 1.88 Impact Factor
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ABSTRACT: In systemic lupus erythematosus, CD4(+) T cells play key roles in the initiation and promotion of autoantigen-specific humoral immunity, and indirect evidence suggests that T cells are pathogenic effectors in lupus nephritis. The contribution of kidney-infiltrating T cells to nephritis, however, has not been verified because of the difficulty in directly analyzing organ-infiltrating T cells. Here, we examined the pathogenic roles of autoreactive cytokine-expressing CD4(+) T cells from the kidneys of early nephritic MRL/lpr mice. Interferon (IFN)-γ-secreting cells were enriched among CD5(high)CD4(+) T cells found in the inflamed kidneys. Using single-cell analysis of the T-cell receptor (TCR)(high)CD5(high)CD4(+) T cells from the kidneys of early nephritic MRL/lpr mice, two IFN-γ-expressing CD4(+) T cell clones, MLK2 and MLK3, were identified. CD4(+) T cells transduced with the T-cell receptor genes from each clone responded to splenic dendritic cells in an MHC class II-dependent manner, but not to B cells or macrophages. MLK3-transduced CD4(+) T cells proliferated in the spleens of prenephritic mice, promoted nephritis progression upon adoptive transfer, and enhanced the deposition of C3 without promoting anti-double-stranded DNA antibody production. Thus, CD4(+) T cells in the inflamed kidneys of MRL/lpr mice contribute to nephritis progression.
Kidney International 07/2012; 82(9):969-79. · 6.61 Impact Factor
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ABSTRACT: A 69-year-old man with sensorineural hearing loss and iritis was diagnosed with atypical Cogan's syndrome. He had several systematic manifestations: aortitis, meningitis, panniculitis and seronegative arthritis. Remission induced by treatment with high doses of prednisolone was followed by relapse within 1 year. Although his condition was resistant to various immunosuppressive drugs, including methotrexate, cyclosporine, azathioprine and adalimumab, his symptoms, inflammatory response and quality of life measures were successfully improved by tocilizumab, a humanized anti-interleukin-6 receptor antibody.
Modern Rheumatology 07/2012; · 1.58 Impact Factor
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ABSTRACT: Regulatory T cells (Tregs) participate in the maintenance of tolerance to self-antigens and suppressive control of excessive immune responses to exogenous antigens. A lack or dysfunction of these cells is responsible for the pathogenesis and development of many autoimmune diseases. It is well known that CD4 Tregs play a major role in controlling immune responses and can be classified into two main populations: thymus-derived naturally occurring Tregs (nTregs) and induced Tregs (iTregs) generated from CD4(+)CD25(-) precursors in the peripheral lymphoid organs. The most extensively studied Tregs are the nTregs, which express the interleukin 2 (IL-2) receptor CD25 and the transcription factor Forkhead box P3 (Foxp3). On the other hand, iTregs contain multiple heterogeneous subsets, including interleukin (IL)-10-producing CD4 type I Tregs (Tr1 cells) and transforming growth factor -β-producing Th3 cells, and so on. However, the extent of the contribution of iTregs to immunoregulation in normal animals has been difficult to evaluate because of the lack of suitable cell surface markers. It has been found recently that IL-10-secreting iTregs can be delineated as CD4(+)CD25(-)Foxp3(-) T cells that characteristically express both the lymphocyte activation gene-3 (LAG3) and the early growth response gene-2 (EGR2). In this review, opinions about the roles of LAG3 and EGR2 in Tregs are presented.
Annals of the rheumatic diseases 04/2012; 71 Suppl 2:i96-100. · 8.11 Impact Factor
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Yukinori Okada,
Chikashi Terao,
Katsunori Ikari,
Yuta Kochi,
Koichiro Ohmura,
Akari Suzuki,
Takahisa Kawaguchi,
Eli A Stahl,
Fina A S Kurreeman,
Nao Nishida, [......],
Michiaki Kubo,
Yusuke Nakamura,
Naoyuki Kamatani,
Tsuneyo Mimori,
Robert M Plenge,
Hisashi Yamanaka,
Shigeki Momohara,
Ryo Yamada,
Fumihiko Matsuda, Kazuhiko Yamamoto
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ABSTRACT: Rheumatoid arthritis is a common autoimmune disease characterized by chronic inflammation. We report a meta-analysis of genome-wide association studies (GWAS) in a Japanese population including 4,074 individuals with rheumatoid arthritis (cases) and 16,891 controls, followed by a replication in 5,277 rheumatoid arthritis cases and 21,684 controls. Our study identified nine loci newly associated with rheumatoid arthritis at a threshold of P < 5.0 × 10(-8), including B3GNT2, ANXA3, CSF2, CD83, NFKBIE, ARID5B, PDE2A-ARAP1, PLD4 and PTPN2. ANXA3 was also associated with susceptibility to systemic lupus erythematosus (P = 0.0040), and B3GNT2 and ARID5B were associated with Graves' disease (P = 3.5 × 10(-4) and 2.9 × 10(-4), respectively). We conducted a multi-ancestry comparative analysis with a previous meta-analysis in individuals of European descent (5,539 rheumatoid arthritis cases and 20,169 controls). This provided evidence of shared genetic risks of rheumatoid arthritis between the populations.
Nature Genetics 03/2012; 44(5):511-6. · 35.53 Impact Factor
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Nature Communications 02/2012; 3:676. · 7.40 Impact Factor
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Chikashi Terao,
Koichiro Ohmura,
Katsunori Ikari,
Yuta Kochi,
Etsuko Maruya,
Masaki Katayama,
Kimiko Yurugi,
Kota Shimada,
Akira Murasawa,
Shigeru Honjo, [......],
Keitaro Matsuo,
Kazuo Tajima,
Akari Suzuki, Kazuhiko Yamamoto,
Shigeki Momohara,
Hisashi Yamanaka,
Ryo Yamada,
Hiroo Saji,
Fumihiko Matsuda,
Tsuneyo Mimori
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ABSTRACT: 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.
PLoS ONE 01/2012; 7(7):e40067. · 4.09 Impact Factor
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Yukinori Okada,
Kenichi Shimane,
Yuta Kochi,
Tomoko Tahira,
Akari Suzuki,
Koichiro Higasa,
Atsushi Takahashi,
Tetsuya Horita,
Tatsuya Atsumi,
Tomonori Ishii, [......],
Hisashi Yamanaka,
Yoshinari Takasaki,
Takao Koike,
Takahiko Horiuchi,
Kenshi Hayashi,
Michiaki Kubo,
Naoyuki Kamatani,
Ryo Yamada,
Yusuke Nakamura, Kazuhiko Yamamoto
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ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Although recent genome-wide association studies (GWAS) have contributed to discovery of SLE susceptibility genes, few studies has been performed in Asian populations. Here, we report a GWAS for SLE examining 891 SLE cases and 3,384 controls and multi-stage replication studies examining 1,387 SLE cases and 28,564 controls in Japanese subjects. Considering that expression quantitative trait loci (eQTLs) have been implicated in genetic risks for autoimmune diseases, we integrated an eQTL study into the results of the GWAS. We observed enrichments of cis-eQTL positive loci among the known SLE susceptibility loci (30.8%) compared to the genome-wide SNPs (6.9%). In addition, we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with SLE susceptibility (rs340630; P = 8.3×10(-9), odds ratio = 1.21). The risk A allele of rs340630 demonstrated a cis-eQTL effect on the AFF1 transcript with enhanced expression levels (P<0.05). As AFF1 transcripts were prominently expressed in CD4(+) and CD19(+) peripheral blood lymphocytes, up-regulation of AFF1 may cause the abnormality in these lymphocytes, leading to disease onset.
PLoS Genetics 01/2012; 8(1):e1002455. · 8.69 Impact Factor
