Showing papers by "Atsuo Taniguchi published in 2016"
TL;DR: This study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk and suggested the value of incorporating additional ancestry in MHC fine-mapping.
Abstract: Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA , a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10 −9 ), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1 , explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping.
67 citations
TL;DR: Heritability of RA onset in the Japanese population is estimated to be comparable with that in European populations, compatible with previous overlap of RA susceptibility genes between Japanese and European populations.
Abstract: Objectives: Rheumatoid arthritis (RA) is the most common immune-related inflammatory arthritis affecting 0.5–1.0% of the population. Both genetic and environmental factors are associated with RA onset. Twin studies reported from European countries estimated heritability of RA as 53–65%. However, no twin studies have been reported from Asian countries.Methods: We collected a total of 43 monozygotic and 43 dizygotic twins from 7550 patients with RA and obtained information of RA status in the twin pairs. We characterized RA patients whose twin siblings had RA. Variance components analysis was performed to estimate heritability in RA in the Japanese population.Results: Four and one patients with RA over 43 monozygotic (9.3%) and 43 dizygotic twins (2.3%), respectively, had twin siblings with RA. All the patients whose information of sero-positivity was available and whose twin siblings had RA were sero-positive. Heritability of RA was estimated as 62.2% and 56.1% in the AE and ACE models, respectivel...
33 citations
TL;DR: The largest-ever effect on Asian rheumatoid arthritis across human non-HLA regions at GTF2I is identified by heterogeneity mapping followed by replication studies, and a possible causal variant is pinpointed.
Abstract: Considerable sharing of disease alleles among populations is well-characterized in autoimmune disorders (e.g., rheumatoid arthritis), but there are some exceptional loci showing heterogenic association among populations. Here we investigated genetic variants with distinct effects on the development of rheumatoid arthritis in Asian and European populations. Ancestry-related association heterogeneity was examined using Cochran’s homogeneity tests for the disease association data from large Asian (n = 14,465; 9,299 discovery subjects and 5,166 validation subjects; 4 collections) and European (n = 45,790; 11 collections) rheumatoid arthritis case-control cohorts with Immunochip and genome-wide SNP array data. We identified significant heterogeneity between the two ancestries for the common variants in the GTF2I locus (PHeterogeneity = 9.6 × 10−9 at rs73366469) and showed that this heterogeneity was due to an Asian-specific association effect (ORMeta = 1.37 and PMeta = 4.2 × 10−13 in Asians; ORMeta = 1.00 and PMeta = 1.00 in Europeans). Trans-ancestral comparison and bioinfomatics analysis revealed a plausibly causal or disease-variant-tagging SNP (rs117026326; in linkage disequilibrium with rs73366469), whose minor allele is common in Asians but rare in Europeans. In conclusion, we identified largest-ever effect on Asian rheumatoid arthritis across human non-HLA regions at GTF2I by heterogeneity mapping followed by replication studies, and pinpointed a possible causal variant.
23 citations
TL;DR: This study clearly demonstrated the distribution of EQ-5D score in the daily practice of RA patients, and provides important information for the pharmacoeconomical studies in rheumatology.
Abstract: Objective. Along with the advances of newly developed medical therapies in rheumatoid arthritis (RA), the number of pharmacoeconomical issues has been paid attention rapidly. For cost–utility analysis and determination of quality-adjusted life years, measurement of the EuroQol 5-dimensional descriptive system (EQ-5D) is essential, and has been used in several clinical studies. However, EQ-5D utility measure in Japanese patients with RA, especially in daily practice has not been fully documented. We analyzed the distribution of EQ5D utility scores and investigated the relationship between other clinical measures based on our Institute of Rheumatology, Rheumatoid Arthritis (IORRA) database.Method. Among 5,284 outpatients who participated in the IORRA cohort study on October 2007, data from 5,043 patients who completed the EQ-5D questionnaire were cross-sectionally analyzed. EQ-5D scores in each subgroup for baseline feature such as gender, age, disease activity score 28 (DAS28), and Japanese version of heal...
18 citations
TL;DR: It is revealed that longer operative time was the risk factor associated with delayed wound healing in RA patients undergoing forefoot surgery, and this finding emphasizes the importance of preventing operative complications during fore foot surgery.
Abstract: Objectives. Forefoot deformities are common in patients with rheumatoid arthritis (RA) and often require operative treatment. There is a high rate of delayed wound healing after foot surgery, especially among patients with RA. The aim of this study was to identify risk factors of delayed wound healing in RA patients who had undergone forefoot surgery.Methods. This study was a retrospective observational study designed to analyze the outcomes of all consecutive RA patients who had undergone toe arthroplasty from April 2010 through May 2014 at a single institute. Putative risk factors for delayed wound healing were assessed using univariate logistic regression analysis. Variables with α = 0.1 were then subjected to stepwise multivariate logistic regression analysis.Results. A total of 192 RA patients (192 feet) were included in this study. Delayed wound healing was seen in 40 feet (40/192 [20.8%]). A stepwise multivariate logistic regression analysis revealed that longer operative time was the risk factor a...
17 citations
TL;DR: Better control of rheumatoid arthritis with a smaller daily prednisolone dose in elderly patients with a history of fractures may be important for preventing proximal humerus fractures.
Abstract: To our knowledge, no prior report focused on the risk factors for proximal humerus fractures in patients with rheumatoid arthritis. The purpose of this study was to evaluate the association between potential risk factors and the occurrence of proximal humerus fractures in patients with rheumatoid arthritis. A total of 11,907 patients with rheumatoid arthritis were enrolled in our observational cohort rheumatoid arthritis study between 2000 and 2012. Self-reported proximal humerus fractures were verified using the patients' medical records. Cox proportional hazard models were used to analyze the independent contribution of risk factors to the occurrence of proximal humerus fractures. During follow-up (mean 5.6 years), 92 proximal humerus fractures were verified in 91 patients. Multivariate Cox regression analyses estimated that the hazard ratios of sustaining a proximal humerus fracture were 1.37 for every 10-year increase in age [95 % confidence interval (CI) 1.10-1.70; P < 0.01], 1.95 for increases in serum C-reactive protein levels (mg/100 mL; 95 % CI 1.15-3.34; P < 0.05), 2.13 for a history of fractures (95 % CI 1.34-3.40; P < 0.01), 1.07 for the daily prednisolone dose (per mg; 95 % CI 1.01-1.13; P < 0.05), and 1.97 for oral bisphosphonate use (95 % CI 1.20-3.23; P < 0.01). Better control of rheumatoid arthritis with a smaller daily prednisolone dose in elderly patients with a history of fractures may be important for preventing proximal humerus fractures.
14 citations
TL;DR: Fracture is a major complication in patients with rheumatoid arthritis (RA) and falls are a major cause of RA fracture as discussed by the authors, which indicated that the p...
Abstract: Fracture is a major complication in patients with rheumatoid arthritis (RA) [1,2]. We previously showed that a major cause of fractures in patients with RA was falls [1], which indicated that the p...
8 citations
TL;DR: TAC may provide a potential therapeutic option for RA patients with moderate to high disease activity and may be effective in comparison with methotrexate or biologics in propensity score-matched rheumatoid arthritis patients.
Abstract: Objective: To analyze the effectiveness of tacrolimus (TAC) in comparison with methotrexate (MTX) or biologics in propensity score (PS)-matched rheumatoid arthritis (RA) patients.Methods: RA patients with moderate or high disease activity as defined by the 28-joint disease activity score (DAS28) and who had completed at least two successive biannual RA cohort surveys were analyzed. Patients were assigned in a stepwise fashion to one of four groups (Biologics, MTX, TAC, or Control) according to medication changes during a 6-month period. A PS was generated for each of three conditions (Biologics, MTX or Control group versus the TAC group, respectively), followed by the assignment of PS-matched patients. At 1 year, the DAS28 in each treatment versus TAC group was analyzed using a mixed effect model with repeated measures.Results: Compared with the respective PS-matched TAC group, the difference in DAS28 at 1 year was −0.398 [95% confidence interval (CI) − 0.660 to −0.136, p < 0.005] in the Biologics...
8 citations
TL;DR: This work identified the largest effect on Asian RA across human non-HLA regions at GTF2I by heterogeneity mapping followed by replication studies, and pinpointed a possible causal variant.
Abstract: Background Genetic association studies using multiple ancestral cohorts have revealed a large overlap of rheumatoid arthritis (RA)-risk alleles among different ancestries, but there are some exceptional loci showing heterogenic association among populations. Objectives Here we investigated genetic variants with distinct effects on the development of RA in Asian and European populations. Methods Ancestry-related association heterogeneity was examined using the association data from large Korean (n=9,299) and European (n=45,790) rheumatoid arthritis cohorts with Immunochip and genome-wide SNP array data. Novel disease associations detected in Koreans were validated using two independent Asian cohorts (n=5,166) and a meta-analysis. Results We identified significant heterogeneity between the two ancestries for the common variants in the GTF2I locus and showed that this heterogeneity is due to an Asian-specific association effect ( P Heterogeneity =9.6×10 -9 at rs73366469 [OR Meta =1.37 and P Meta =4.2×10 –13 in Asians; OR Meta =1.00 and P Meta =1.00 in Europeans]) in RA. Trans-ancestral comparison and bioinfomatics analysis revealed a plausibly causal SNP (rs117026326; linked to rs73366469), whose minor allele is common in Asians but rare in Europeans. Conclusions We identified the largest effect on Asian RA across human non-HLA regions at GTF2I by heterogeneity mapping followed by replication studies, and pinpointed a possible causal variant. References Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–81 (2014). Kim, K. et al. High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci. Ann Rheum Dis 74, e13 (2015). Acknowledgement This study was supported by the Korea Healthcare Technology R&D Project of the Ministry for Health & Welfare (HI13C2124), the Japanese Ministry of Education, Culture, Sports, Science and Technology Grant-in-Aid for Scientific Research (15H04965) and the US National Institutes of Health (R01MD007909 and R01AR060366). *Drs. Kwangwoo Kim and So-Young Bang contributed equally to this work. Disclosure of Interest None declared
5 citations
TL;DR: Higher disease activity was a risk factor for overall malignancies, lung cancer and malignant lymphoma in Japanese patients with RA, however, treatment with MTX and biological agents was not a risk factors for malignancy.
Abstract: Background As treatments for rheumatoid arthritis (RA) such as methotrexate (MTX) and biological agents have made dramatic progress in this decade, it is desirable to improve patient quality of life and prognosis, including management of various comorbidities. Malignancy is an important comorbidity in patients with RA1,2. No significant difference in the overall incidence of malignancies in Japanese patients with RA (standardized incidence ratio [SIR] 0.96, 95% confidence interval [CI] 0.90–1.03) was noted compared with the general Japanese population3. However, a markedly significant increase in the incidence of malignant lymphoma was observed (SIR 5.10, 95% CI 4.21–6.13), and the incidence of lung cancer in males was also increased significantly3. In contrast, the incidence of gastric cancer and colorectal cancer was decreased significantly3. It is important to investigate the risk factors for malignancies to examine the prognosis of patients with RA. Objectives To investigate the risk factors for overall and site-specific malignancies in a large observational cohort of Japanese patients with RA over a long-term period. Methods Among Japanese patients with RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort from April 2000 to September 2013, all malignancies were extracted from patients9 self-reporting and confirmed by medical records. Patients who dropped out of the IORRA cohort were asked about comorbidities, including malignancies, by follow-up mail. With regard to overall malignancies and malignancies at frequently involved sites (lung cancer, malignant lymphoma, breast cancer, gastric cancer and colorectal cancer), risk factors were analysed with time-dependent Cox regression adjusted by age, gender, smoking history and BMI. Results Among 11,106 Japanese patients with RA representing 122,706 person-years, a total of 830 overall malignancies, including 114 lung cancers, 114 malignant lymphomas, 105 breast cancers, 95 gastric cancers and 90 colorectal cancers, were confirmed. RA disease duration was a significant risk factor for lung cancer (hazard ratio [HR] 0.95, P =0.001) and malignant lymphoma (HR 0.95, P =0.004). RF positivity was a significant risk factor for lung cancer (HR 2.26, P =0.018). DAS28 score was a significant risk factor for overall malignancies (HR 1.10, P =0.008), lung cancer (HR 1.25, P =0.012) and malignant lymphoma (HR 1.22, P =0.049). Neither MTX nor biological agent use was a significant risk factor for overall malignancies or malignancies at specific sites. Conclusions Higher disease activity was a risk factor for overall malignancies, lung cancer and malignant lymphoma in Japanese patients with RA. However, treatment with MTX and biological agents was not a risk factor for malignancy. These results suggest that tight control of RA disease activity would protect against the occurrence of malignancies in patients with RA. References Gullick NJ, et al. Best Pract Res Clin Rheumatol. 2011;25:469–83. Nakajima A, et al. Scand J Rheumatol. 2010;39:360–7. Sugimoto N, et al. EULAR Congress 2015;THU0161. Disclosure of Interest N. Sugimoto: None declared, E. Tanaka Speakers bureau: ET has received speaker fees or consulting fees from Abbvie, Eisai Pharmaceutical, Chugai Pharmaceutical, Bristol Myers Squibb, Astellas Pharmaceutical, Pfizer, Takeda Pharmaceutical, and Santen Pharmaceutical., E. Inoue: None declared, Y. Shimizu: None declared, K. Shidara: None declared, A. Nakajima: None declared, A. Taniguchi: None declared, S. Momohara Speakers bureau: SM has received speaker fees from Abbott, AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Eisai, Mitsubishi Tanabe, Pfizer, Takeda, and Teijin., H. Yamanaka Speakers bureau: HY has received speaker fees from Abbott, AbbVie, Asahikasei, Astellas, AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, MSD, Nippon Kayaku, Pfizer, Santen, Taishotoyama, Takeda, and Teijin.
1 citations
TL;DR: Centromere pattern-positive rheumatoid arthritis is a distinct subset with specific clinical features and complications and a possibly new risk factor of bone destruction in RA.
Abstract: Objectives Centromere pattern is a staining pattern of anti-nuclear antibodies (ANAs). Here, we characterize the titer distribution of centromere pattern and analyze clinical and genetic features of centromere pattern-positive rheumatoid arthritis (RA). Methods We examined ANA by indirect immunofluorescence for 9,575 healthy volunteers and 1,211 RA patients without systemic sclerosis in Kyoto University Hospital. HLA-DRB1 was genotyped for 285 RA patients. We compared distributions of titers among ANA and analyzed associations between centromere pattern and clinical or genetic features in the subjects. For validation, we recruited another cohort of 2,424 RA patients in Tokyo Woman9s Medical University Hospital to confirm the associations between centromere pattern and clinical features. Results Eighty seven healthy volunteers (0.91%) and 25 RA patients (2.76%) were positive for centromere pattern of ANA. Centromere pattern was the only ANA staining pattern that demonstrated a definite bimodal distribution of levels in both healthy volunteers and patients with RA. Centromere pattern showed significantly higher levels than the other ANA patterns in the subjects positive for each ANA (p Centromere pattern-positive patients with RA showed lower positivity of rheumatoid factor (RF) (p=0.0011) that is one of risk factors for bone destruction. Centromere pattern was associated with Raynaud9s phenomenon and complication of Sjogren9s syndrome and primary biliary cirrhosis (p≤0.0052). No HLA-DRB1 alleles were significantly associated with centromere pattern. In validation study, 82 RA patients (2.41%) were positive for centromere pattern. Centromere pattern-positivity was again associated with old age, females and negativity of RF (p≤0.0044). Information of complications and symptoms was not available in the replication cohort. Centromere pattern-positive patients tended to show higher Total Sharp Score in spite of lower frequencies of RF in both cohorts. Conclusions Centromere pattern showed a specific distribution of levels among ANA. Centromere pattern-positive RA is a distinct subset with specific clinical features and complications. Centromere pattern is a possibly new risk factor of bone destruction in RA. Disclosure of Interest None declared