Yuta Kochi

The University of Tokyo, 白山, Tōkyō, Japan

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Publications (54)489.1 Total impact

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    ABSTRACT: Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10(-117), odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.
    Full-text · Article · Jan 2016 · Nature Genetics
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    ABSTRACT: Rheumatoid arthritis (RA) is a common autoimmune disease that results in significant morbidity. As with other complex disorders, genome-wide association studies (GWASs) have greatly contributed to the current understanding of RA etiology. In this review, we describe the genetic configuration of RA as revealed primarily through GWASs and their meta-analyses. In addition, we discuss the pathologic mechanisms of RA as suggested by the findings of genetic and functional studies of individual RA-associated genes, including HLA-DRB1, PADI4, PTPN22, CCR6 and FCRL3, and the potential use of genetic information for RA treatment in clinical practice.
    No preview · Article · Oct 2015 · Proceedings of the Japan Academy Ser B Physical and Biological Sciences
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    ABSTRACT: Rheumatoid arthritis (RA) is an autoimmune destructive arthritis associated with CD4(+) T cell-mediated immunity. Although expanded CD4(+) T cell clones (ECs) has already been confirmed, the detailed characteristics of ECs have not been elucidated in RA. Using combination of a single-cell analysis and next-generation sequencing (NGS) in TCR repertoire analysis, we here revealed the detailed nature of ECs by examining peripheral blood (PB) from 5 RA patients and synovium from 1 RA patient. When we intensively investigated the single-cell transcriptome of the most expanded clones in memory CD4(+) T cells (memory-mECs) in RA-PB, senescence-related transcripts were up-regulated, indicating circulating ECs were constantly stimulated. Tracking of the transcriptome shift within the same memory-mECs between PB and the synovium revealed the augmentations in senescence-related gene expression and the up-regulation of synovium-homing chemokine receptors in the synovium. Our in-depth characterization of ECs in RA successfully demonstrated the presence of the specific immunological selection pressure, which determines the phenotype of ECs. Moreover, transcriptome tracking added novel aspects to the underlying sequential immune processes. Our approach may provide new insights into the pathophysiology of RA.
    Preview · Article · Aug 2015 · Scientific Reports
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    ABSTRACT: Takayasu arteritis (TAK) is a systemic vasculitis affecting large arteries and large branches of the aorta. Ulcerative colitis (UC) is a prevalent autoimmune colitis. Since TAK and UC share HLA-B*52:01 and IL12B for genetic determinants as well as concurrent case reports for these two diseases, we hypothesized that UC is a common complication of TAK. We performed a large scale analysis of TAK to evaluate concurrence ratio of TAK and UC and to estimate shared susceptibility genes between the two diseases Methods: A total of 470 consecutive patients with TAK from 14 institutions were analyzed. We characterized patients with TAK and UC by analyzing clinical manifestations and genetic components. Genetic overlapping of TAK and UC was evaluated with use of UC susceptibility SNPs by comparing risk directions and effect sizes between susceptibility to the two diseases. 30 out of 470 patients with TAK suffered from UC (6.4% (95%CI:4.3%-9.0%)). This ratio was strikingly higher than that expected from prevalence of UC. Patients with TAK complicated with UC developed TAK at an earlier stage of life (p=0.0070) and showed significant enrichment of HLA-B*52:01 in comparison to TAK patients without UC (p=1.0x10(-5) , OR:12.14, 95%CI:2.96-107.23). The 110 susceptibility non-HLA loci to UC displayed common risk directions with TAK susceptibility (p=0.0054) and significant departure of permutation p-values from expected p-values (p<1.0x10(-10) ). UC is a major complication of TAK. These two diseases share a significant proportion of their genetic background and HLA-B*52:01 may play a central role on the concurrence. This article is protected by copyright. All rights reserved. © 2015 American College of Rheumatology.
    Full-text · Article · May 2015 · Arthritis & Rheumatology
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    ABSTRACT: Although susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA. We intended to elucidate genetic background of ACPA-negative RA. 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 single nucleotide polymorphisms (SNPs) using 916 cases and 3,764 controls. Inverse-variance method was applied to assess overall effects. To assess overlap of susceptibility loci 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. Rs6904716 in LEMD2 of the human leukocyte antigen (HLA) locus showed a borderline association with ACPA-negative RA (overall p = 5.7 × 10(-8)), followed by rs6986423 in CSMD1 (p = 2.4 × 10(-6)) and rs17727339 in FCRL3 (p = 1.4 × 10(-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. Many of the susceptibility loci were shared between ACPA-positive and -negative RA.
    Full-text · Article · Apr 2015 · Arthritis research & therapy
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    ABSTRACT: Anti-citrullinated peptide antibody (ACPA) is an autoantibody that is highly specific to rheumatoid arthritis (RA). Strong associations have been detected between HLA-DRB1 alleles and ACPA levels in RA patients. However, the associations between particular amino acid positions in HLA-DRB1 and RA patients' ACPA levels are largely unknown. We analyzed ACPA data for a total of 4,371 Japanese ACPA(+) RA patients in whom HLA-DRB1 allele genotyping had been performed. Generalized linear regression analysis and omnibus test were carried out to determine the associations between HLA-DRB1 alleles, amino acid residues or positions and ACPA levels. HLA-DRB1*09:01 and HLA-DR15 were confirmed to be associated with ACPA levels. DRB1*08:03 and DRB1*14:06 were associated with reduced and increased ACPA levels, respectively. We detected a strong association between ACPA levels and amino acid position 74 (p=1.9x10(-51) ). The association was mainly brought by alanine residue (p=5.1x10(-51) ). After adjusting for the 74(th) position, the amino acid positions 60 and 57 were found to be associated with the ACPA level. The 74(th) and 57(th) amino acid positions were previously reported to be associated with susceptibility to ACPA(+) RA in Asians. The combination of the 74(th) and 60(th) or 57(th) amino acid residues displayed improvements in fit as the models comparable to all of the significant HLA-DRB1 alleles. The 74(th) amino acid position in HLA-DRB1 is strongly associated with the ACPA level in ACPA(+) RA as well as RA susceptibility. The mechanisms of ACPA(+) RA susceptibility and ACPA production seem to partly overlap. This article is protected by copyright. All rights reserved. © 2015 American College of Rheumatology.
    No preview · Article · Apr 2015 · Arthritis and Rheumatology
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    ABSTRACT: Genome-wide association studies (GWAS) have uncovered numerous susceptibility genes for rheumatoid arthritis (RA) in patients of European, Asian and other ethnic ancestries. Although previous transethnic GWAS meta-analyses enabled the identification of several novel loci, the genetic heterogeneity observed in the PADI4 and PTPN22 genes suggests that ethnic variation should be considered. In addition, the effects of genetic polymorphisms on gene expression profiles are important when assessing the association of genetic information with disease pathogenesis and will influence the development of personalized medicine. Gene expression is controlled by epigenetic modifications, which in turn can be affected by environmental stimuli. Altogether, genetic and epigenetic information of Asian populations will contribute considerably to future rheumatology research.
    No preview · Article · Feb 2015 · Nature Reviews Rheumatology
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    Yuta Kochi · Akari Suzuki · Kazuhiko Yamamoto
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    ABSTRACT: Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. As with other complex traits, genome-wide association studies (GWASs) have tremendously enhanced our understanding of the complex etiology of RA. In this review, we describe the genetic architecture of RA as determined through GWASs and meta-analyses. In addition, we discuss the pathologic mechanism of the disease by examining the combined findings of genetic and functional studies of individual RA-associated genes, including HLA-DRB1, PADI4, PTPN22, TNFAIP3, STAT4, and CCR6. Moreover, we briefly examine the potential use of genetic data in clinical practice in RA treatment, which represents a challenge in medical genetics in the post-GWAS era.
    Preview · Article · Jul 2014 · Biochemical and Biophysical Research Communications
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    ABSTRACT: 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. 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
    No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: In rheumatoid arthritis (RA), smoking has been described to be specifically associated with the presence of anti-citrullinated protein antibodies (ACPA). However, smoking has also been shown to be associated with the presence of autoantibodies in various other autoimmune diseases, such anti-dsDNA in systemic lupus erythematosus and anti-Jo1 in idiopathic inflammatory myopathy. We therefore investigated whether smoking is specifically associated with ACPA-positive RA, or with autoantibody-positive RA in general. A meta-analysis was performed using RA patients from 5 countries: Norway, the Netherlands, Japan, Sweden, and the United Kingdom. Complete data on rheumatoid factor (RF)-, ACPA-status and tobacco exposure were available for 6320 RA patients. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the presence of RF, ACPA or both, were calculated by logistic regression comparing ever smokers with never smokers, and using the RF-negative ACPA-negative RA patients as the reference category. There was no significant association between smoking and RA in patients who were positive for only one antibody, being either RF (OR 1.04, 0.76 - 1.42) or ACPA (OR 1.00, 0.82 - 1.22). However, smoking was significantly associated with double-positive (RF-positive and ACPA-positive) RA (OR 1.55, 1.20 - 2.00). When ANA-status was also taken into account in the Dutch cohort, the association with smoking was strongest for the triple-positive group (OR = 2.43, 95% CI 1.47 - 4.00), although the difference with the double-positive RA patients (RF- and ACPA-positive, ANA-negative) (OR = 1.73, 95% CI 1.14 - 2.62) was not statistically significant. Smoking is not specifically associated with ACPA-positive RA, but rather with the concurrent presence of RF and ACPA in RA patients. These data indicate that smoking predisposes to the development of several autoantibodies, and that current hypotheses about the role of smoking in the pathophysiology of RA may need to be revisited.
    No preview · Article · Mar 2014 · Annals of the rheumatic diseases
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    ABSTRACT: 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. Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Smoking is associated with the presence of autoantibodies in various diseases, such as chronic obstructive pulmonary disease (COPD)1, systemic lupus erythematosus (SLE)2 and polymyositis3. In rheumatoid arthritis (RA), smoking is assumed to be specifically associated with the presence of anti-citrullinated protein antibodies (ACPA), with smoking putatively leading to increased pulmonary citrullination. 4 Objectives To investigate whether the association of smoking with RA is limited to ACPA-positive disease, or whether smoking is associated with autoantibody-positive RA in general. Methods A meta-analysis based partly on published data (2 cohorts)4,5, and partly on new data (4 cohorts) was performed using 6 cohorts of RA patients from 5 countries: United Kingdom, Sweden, Norway, Japan, and the Netherlands. Complete data on rheumatoid factor (RF)-, ACPA-status and tobacco exposure were available for 7055 RA patients. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the presence of RF, ACPA or both were calculated by logistic regression comparing previous and current smokers with non-smokers, and using the ACPA-negative RF-negative RA patients as the reference category, since not all cohorts had matched controls. Results There was no significant association between tobacco exposure and seropositive RA in patients who were positive for only one antibody, being either RF (n = 644, OR 1.04, 95% CI 0.75 – 1.44) or ACPA (n = 770, OR 1.00, 95% CI 0.83 – 1.22). However, smoking was significantly associated with double-positive (ACPA-positive and RF-positive) RA (n = 3598, OR 1.61, 95% CI 1.31 – 2.00). When double-positive patients were compared to single-positive patients, the effect of the additional presence of RF or ACPA was comparable; OR for RF: 1.42 (1.20 – 1.67), OR for ACPA: 1.49 (1.25 – 1.87). Conclusions Smoking is not associated with ACPA-positive RA as such, but rather with the concurrent presence of multiple autoantibodies (RF and ACPA) in RA patients. In light of the association between smoking and autoantibodies in other diseases such as SLE and COPD, these data indicate that smoking predisposes to the development of auto-antibodies in general, and not to the development of ACPA per se. References Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
    Full-text · Article · Dec 2013 · Nature
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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 χ2 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.
    Full-text · Article · Feb 2013 · Rheumatology (Oxford, England)
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    ABSTRACT: Objective: 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, our group identified 9 novel susceptibility genes associated with rheumatoid arthritis (RA) in a Japanese population. The aim of this study was to elucidate whether the 18 genes that displayed associations or suggestive associations for RA in our previous study are associated with SSc in Japanese. Methods: We performed an association study that included 415 patients with SSc and 16,891 control subjects, followed by a replication study that included 315 patients and 21,054 control subjects. The 18 markers reported to display association with RA were analyzed for their associations with SSc in the first study, and 5 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: In the phospholipase D4 gene (PLD4), rs2841277 displayed a significant association with SSc in Japanese patients (P = 0.00017). We observed that rs2841280 in exon 2 of PLD4 was in strong linkage disequilibrium with rs2841277 and introduced an amino acid alteration. We also observed associations between SSc and rs6932056 in TNFAIP3 and rs2280381 in IRF8 (P = 0.0000095 and P = 0.0030, respectively), both of which displayed associations with SSc in a European population. Conclusion: We determined that PLD4 is a novel susceptibility gene for SSc in Japanese, thus confirming the involvement of PLD4 in autoimmunity. Associations between SSc and TNFAIP3 or IRF8 were also detected in our Japanese population. SSc and RA appear to share relatively large proportions of their genetic backgrounds.
    No preview · Article · Feb 2013 · Arthritis & Rheumatology
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    ABSTRACT: Author Summary Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting approximately 1% of the general adult population. More than 30 susceptibility loci for RA have been identified through genome-wide association studies (GWAS), but the disease-causal variants at most loci remain unknown. Here, we performed replication studies of the candidate loci of our previous GWAS using Japanese cohorts and identified variants in NFKBIE and RTKN2 gene loci that were associated with RA. To search for causal variants in both gene regions, we first examined non-synonymous (ns)SNPs that alter amino-acid sequences. As NFKBIE and RTKN2 are known to be involved in the NF-κB pathway, we evaluated the effects of nsSNPs on NF-κB activity. Next, we screened in silico variants that may regulate gene transcription using publicly available epigenetic databases and subsequently evaluated their regulatory potential using in vitro assays. As a result, we identified multiple candidate causal variants in NFKBIE (2 nsSNPs and 1 regulatory SNP) and RTKN2 (2 regulatory SNPs), indicating that our integrated in silico and in vitro approach is useful for the identification of causal variants in the post–GWAS era.
    Full-text · Article · Sep 2012 · PLoS Genetics
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    Full-text · Article · Aug 2012 · The Journal of Rheumatology
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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.
    Full-text · Article · Jul 2012 · PLoS ONE
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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.
    Full-text · Article · Mar 2012 · Nature Genetics
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    ABSTRACT: We have previously shown that rheumatoid arthritis (RA) risk alleles overlap between different ethnic groups. Here, we utilize a multiethnic approach to show that we can effectively discover RA risk alleles. Thirteen putatively associated SNPs that had not yet exceeded genome-wide significance (p < 5 × 10(-8)) in our previous RA genome-wide association study (GWAS) were analyzed in independent sample sets consisting of 4,366 cases and 17,765 controls of European, African American, and East Asian ancestry. Additionally, we conducted an overall association test across all 65,833 samples (a GWAS meta-analysis plus the replication samples). Of the 13 SNPs investigated, four were significantly below the study-wide Bonferroni corrected p value threshold (p < 0.0038) in the replication samples. Two SNPs (rs3890745 at the 1p36 locus [p = 2.3 × 10(-12)] and rs2872507 at the 17q12 locus [p = 1.7 × 10(-9)]) surpassed genome-wide significance in all 16,659 RA cases and 49,174 controls combined. We used available GWAS data to fine map these two loci in Europeans and East Asians, and we found that the same allele conferred risk in both ethnic groups. A series of bioinformatic analyses identified TNFRSF14-MMEL1 at the 1p36 locus and IKZF3-ORMDL3-GSDMB at the 17q12 locus as the genes most likely associated with RA. These findings demonstrate empirically that a multiethnic approach is an effective strategy for discovering RA risk loci, and they suggest that combining GWASs across ethnic groups represents an efficient strategy for gaining statistical power.
    Full-text · Article · Feb 2012 · The American Journal of Human Genetics

Publication Stats

2k Citations
489.10 Total Impact Points

Institutions

  • 2004-2015
    • The University of Tokyo
      • • Department of Allergy and Rheumatology
      • • Center for Human Genome
      白山, Tōkyō, Japan
    • RIKEN
      • Laboratory for Autoimmune Diseases
      Вако, Saitama, Japan
  • 2005
    • Toyota Physical and Chemical Institute
      Seto, Aichi, Japan
    • Hanyang University
      • Major in Internal Medicine
      Sŏul, Seoul, South Korea