The Experts below are selected from a list of 13890465 Experts worldwide ranked by ideXlab platform
Naoyuki Tsuchiya - One of the best experts on this subject based on the ideXlab platform.
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Human CD72 splicing isoform responsible for resistance to systemic lupus erythematosus regulates serum immunoglobulin level and is localized in endoplasmic reticulum
BMC immunology, 2012Co-Authors: Yuki Hitomi, Takahiro Adachi, Naoyuki Tsuchiya, Zen-ichiro Honda, Katsushi Tokunaga, Takeshi TsubataAbstract:Background CD72 is an inhibitory co-receptor expressed on B cells. We previously demonstrated significant association of the polymorphism of the CD72 gene with susceptibility to human systemic lupus erythematosus (SLE) in individuals carrying a SLE-susceptible FCGR2B genotype (FCGR2B-232Thr/Thr). The human CD72 locus generates a splicing isoform that lacks exon 8 (CD72Δex8) as well as full-length CD72 (CD72fl), and the CD72 polymorphism regulates exon 8 skipping.
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Role of B cell inhibitory receptor polymorphisms in systemic lupus erythematosus: a negative times a negative makes a positive
Journal of Human Genetics, 2006Co-Authors: Naoyuki Tsuchiya, Zen-ichiro Honda, Katsushi TokunagaAbstract:B lymphocytes play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). Here, we will review our studies on the role of polymorphisms of two genes coding for B cell inhibitory receptors, FCGR2B and CD72 . In FCGR2B , a single nucleotide polymorphism leading to a nonsynonymous substitution, Ile232Thr, within the transmembrane domain was identified, and a significant association of the 232Thr/Thr genotype with SLE was observed in Japanese, Thai and Chinese populations, while this allele was found to be rare in Caucasians. On the other hand, the association of FCGR2B promoter polymorphism with SLE in Caucasians has been reported by two independent groups, but this allele was not found to be present in Japanese. These observations demonstrate that the association of FCGR2B polymorphisms with SLE is common to multiple populations, but the alleles associated with SLE depend upon the genetic background of each population. Functional analyses using a human B cell line lacking endogenous FcγRIIb revealed that SLE-associated 232Thr allele product was partially excluded from membrane lipid rafts under resting conditions and after coligation with B cell receptor, and was significantly less potent at inhibiting B cell activation. Two haplotypes were identified in CD72 , one of which was associated with increased production of an alternative splicing isoform that substantially alters the extracellular region of CD72. Interestingly, the presence of the haplotype significantly decreased the risk of SLE conferred by FCGR2B -232Thr in an epistatic manner. These observations emphasize the need to understand human immune system diversity if we are to improve our understanding of the pathogenesis of autoimmune diseases.
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Role of Fcγ receptor IIb polymorphism in the genetic background of systemic lupus erythematosus: Insights from Asia
Autoimmunity, 2005Co-Authors: Naoyuki Tsuchiya, Chieko KyogokuAbstract:FCGR2B codes for an inhibitory receptor expressed in B cells and monocytes. Polymorphisms of FCGR2B in mice have been shown to be associated with autoimmune diseases including systemic lupus erythematosus (SLE) and targeted disruption of FCGR2B renders mice susceptible to induced or spontaneous autoimmunity, depending on the genetic background. Polymorphism screening of FCGR2B has been hampered by the complexity and extreme homology among FCGR family members. We established a specific genotyping system, detected a SNP that changes position 232 amino acid in the transmembrane region from Ile to Thr and found a significant association of 232Thr with SLE in the Japanese, Thai and Chinese populations. In contrast, promoter polymorphism of FCGR2B, but not Ile232Thr, was shown to be associated with SLE in Caucasians. Linkage disequilibrium was observed among FCGR2A, 2B, 3A and 3B genes with varying degrees, but in the Asian populations, each of FCGR2B, 3A and 3B genes was suggested to contribute to the susceptibility to SLE. These results indicate that FCGR2B is a susceptibility gene to SLE in the context of a genetic background, both in humans and mice.
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CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B
Human molecular genetics, 2004Co-Authors: Yuki Hitomi, Chieko Kyogoku, Naoyuki Tsuchiya, Jun Ohashi, Toru Fukazawa, Aya Kawasaki, Takeshi Suzuki, Sasitorn Bejrachandra, Usanee Siriboonrit, D. ChandanayingyongAbstract:We previously reported association of FCGR2B-Ile232Thr with systemic lupus erythematosus (SLE) in three Asian populations. Because polymorphism of CD72, another inhibitory receptor of B cells, was associated with murine SLE, we identified human CD72 polymorphisms, tested their association with SLE and examined genetic interaction with FCGR2B in the Japanese (160 SLE, 277 controls), Thais (87 SLE, 187 controls) and Caucasians (94 families containing SLE members). Four polymorphisms and six rare variations were detected. The former constituted two major haplotypes that contained one or two repeats of 13 nucleotides in intron 8 (designated as *1 and *2, respectively). Although association with susceptibility to SLE was not detected, the *1 allele was significantly associated with nephritis among the Japanese patients (P = 0.024). RT-PCR identified a novel alternatively spliced (AS) transcript that was expressed at the protein level in COS-7 transfectants. The ratio of ASlcommon isoforms was strikingly increased in individuals with *2/*2 genotype when compared with *1/*1 (P = 0.000038) or *1/*2 (P = 0.0085) genotypes. Using the two Asian cohorts, significant association of FCGR2B-232Thr/Thr with SLE was observed only in the presence of CD72-*1/*1 genotype (OR 4.63, 95% CI 1.47-14.6, P = 0.009 versus FCGR2B-232Ile/Ile plus CD72-*2/*2). Minigene assays demonstrated that the 13-nucleotide repeat and 4 bp deletion within the same haplotype of intron 8 could regulate alternative splicing. The AS isoform lacks exon 8, and is deduced to contain 49 amino acid changes in the membrane-distal portion of the extracellular domain, where considerable amino acid changes are known in CD72 c allele associated with murine SLE. These results indicated that the presence of CD72-*2 allele decreases risk for human SLE conferred by FCGR2B-232Thr, possibly by increasing the AS isoform of CD72.
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Association of Fcγ receptor IIb polymorphism with susceptibility to systemic lupus erythematosus in Chinese: a common susceptibility gene in the Asian populations
Tissue antigens, 2004Co-Authors: Z.t. Chu, Chieko Kyogoku, Naoyuki Tsuchiya, Jun Ohashi, Ya-ping Qian, C.z. Mao, J. Y. Chu, Katsushi TokunagaAbstract:The association of Fcgamma receptor (FcgammaR) polymorphisms with systemic lupus erythematosus (SLE) has been demonstrated in various populations; however, the results have been inconsistent. We recently identified a single-nucleotide polymorphism encoding a non-synonymous substitution, Ile232Thr (I232T), of FCGR2B and its association with SLE in Japanese and in Thais. Multiple functional FcgammaR genes with polymorphisms (FCGR2A, FCGR2B, FCGR3A, and FCGR3B) cluster in 1q23, and some of them are in linkage disequilibrium (LD). To differentiate contributions from multiple-linked loci, comparison of different populations may provide useful information. In this study, we analyzed the above four FCGR polymorphisms of the Chinese patients and controls for the association with SLE. FCGR2A-H131R, FCGR2B-I232T, FCGR3A-F176V, and FCGR3B genotypes were determined in 167 Chinese patients with SLE and 129 healthy controls. Association was examined using case-control analysis. Allele frequencies of FCGR2B-232T and FCGR3A-176F were significantly increased in SLE [odds ratio (OR) = 1.67 and OR = 1.41, respectively]. Interestingly, while these alleles had a tendency of positive LD in the controls, FCGR2B-232T was in positive association with FCGR3A-176V in SLE, suggesting that these two alleles were associated with SLE in an independent manner. Comparison between SLE with and without nephritis indicated significant association of FCGR2B-232T with nephritis (OR = 2.65). When the present results were combined with our previous data on the Japanese and the Thais using meta-analytic methods, highly significant and independent association was observed for FCGR2B and FCGR3A genotypes. These results strongly suggested that FCGR2B is a common susceptibility factor to SLE in the Asians.
Chieko Kyogoku - One of the best experts on this subject based on the ideXlab platform.
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Role of Fcγ receptor IIb polymorphism in the genetic background of systemic lupus erythematosus: Insights from Asia
Autoimmunity, 2005Co-Authors: Naoyuki Tsuchiya, Chieko KyogokuAbstract:FCGR2B codes for an inhibitory receptor expressed in B cells and monocytes. Polymorphisms of FCGR2B in mice have been shown to be associated with autoimmune diseases including systemic lupus erythematosus (SLE) and targeted disruption of FCGR2B renders mice susceptible to induced or spontaneous autoimmunity, depending on the genetic background. Polymorphism screening of FCGR2B has been hampered by the complexity and extreme homology among FCGR family members. We established a specific genotyping system, detected a SNP that changes position 232 amino acid in the transmembrane region from Ile to Thr and found a significant association of 232Thr with SLE in the Japanese, Thai and Chinese populations. In contrast, promoter polymorphism of FCGR2B, but not Ile232Thr, was shown to be associated with SLE in Caucasians. Linkage disequilibrium was observed among FCGR2A, 2B, 3A and 3B genes with varying degrees, but in the Asian populations, each of FCGR2B, 3A and 3B genes was suggested to contribute to the susceptibility to SLE. These results indicate that FCGR2B is a susceptibility gene to SLE in the context of a genetic background, both in humans and mice.
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CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B
Human molecular genetics, 2004Co-Authors: Yuki Hitomi, Chieko Kyogoku, Naoyuki Tsuchiya, Jun Ohashi, Toru Fukazawa, Aya Kawasaki, Takeshi Suzuki, Sasitorn Bejrachandra, Usanee Siriboonrit, D. ChandanayingyongAbstract:We previously reported association of FCGR2B-Ile232Thr with systemic lupus erythematosus (SLE) in three Asian populations. Because polymorphism of CD72, another inhibitory receptor of B cells, was associated with murine SLE, we identified human CD72 polymorphisms, tested their association with SLE and examined genetic interaction with FCGR2B in the Japanese (160 SLE, 277 controls), Thais (87 SLE, 187 controls) and Caucasians (94 families containing SLE members). Four polymorphisms and six rare variations were detected. The former constituted two major haplotypes that contained one or two repeats of 13 nucleotides in intron 8 (designated as *1 and *2, respectively). Although association with susceptibility to SLE was not detected, the *1 allele was significantly associated with nephritis among the Japanese patients (P = 0.024). RT-PCR identified a novel alternatively spliced (AS) transcript that was expressed at the protein level in COS-7 transfectants. The ratio of ASlcommon isoforms was strikingly increased in individuals with *2/*2 genotype when compared with *1/*1 (P = 0.000038) or *1/*2 (P = 0.0085) genotypes. Using the two Asian cohorts, significant association of FCGR2B-232Thr/Thr with SLE was observed only in the presence of CD72-*1/*1 genotype (OR 4.63, 95% CI 1.47-14.6, P = 0.009 versus FCGR2B-232Ile/Ile plus CD72-*2/*2). Minigene assays demonstrated that the 13-nucleotide repeat and 4 bp deletion within the same haplotype of intron 8 could regulate alternative splicing. The AS isoform lacks exon 8, and is deduced to contain 49 amino acid changes in the membrane-distal portion of the extracellular domain, where considerable amino acid changes are known in CD72 c allele associated with murine SLE. These results indicated that the presence of CD72-*2 allele decreases risk for human SLE conferred by FCGR2B-232Thr, possibly by increasing the AS isoform of CD72.
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Association of Fcγ receptor IIb polymorphism with susceptibility to systemic lupus erythematosus in Chinese: a common susceptibility gene in the Asian populations
Tissue antigens, 2004Co-Authors: Z.t. Chu, Chieko Kyogoku, Naoyuki Tsuchiya, Jun Ohashi, Ya-ping Qian, C.z. Mao, J. Y. Chu, Katsushi TokunagaAbstract:The association of Fcgamma receptor (FcgammaR) polymorphisms with systemic lupus erythematosus (SLE) has been demonstrated in various populations; however, the results have been inconsistent. We recently identified a single-nucleotide polymorphism encoding a non-synonymous substitution, Ile232Thr (I232T), of FCGR2B and its association with SLE in Japanese and in Thais. Multiple functional FcgammaR genes with polymorphisms (FCGR2A, FCGR2B, FCGR3A, and FCGR3B) cluster in 1q23, and some of them are in linkage disequilibrium (LD). To differentiate contributions from multiple-linked loci, comparison of different populations may provide useful information. In this study, we analyzed the above four FCGR polymorphisms of the Chinese patients and controls for the association with SLE. FCGR2A-H131R, FCGR2B-I232T, FCGR3A-F176V, and FCGR3B genotypes were determined in 167 Chinese patients with SLE and 129 healthy controls. Association was examined using case-control analysis. Allele frequencies of FCGR2B-232T and FCGR3A-176F were significantly increased in SLE [odds ratio (OR) = 1.67 and OR = 1.41, respectively]. Interestingly, while these alleles had a tendency of positive LD in the controls, FCGR2B-232T was in positive association with FCGR3A-176V in SLE, suggesting that these two alleles were associated with SLE in an independent manner. Comparison between SLE with and without nephritis indicated significant association of FCGR2B-232T with nephritis (OR = 2.65). When the present results were combined with our previous data on the Japanese and the Thais using meta-analytic methods, highly significant and independent association was observed for FCGR2B and FCGR3A genotypes. These results strongly suggested that FCGR2B is a common susceptibility factor to SLE in the Asians.
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genetic background of japanese patients with antineutrophil cytoplasmic antibody associated vasculitis association of hla drb1 0901 with microscopic polyangiitis
The Journal of Rheumatology, 2003Co-Authors: Naoyuki Tsuchiya, Chieko Kyogoku, Katsushi Tokunaga, Aya Kawasaki, Shigeto Kobayashi, Yoshihiro Arimura, Masaharu Yoshida, Hiroshi HashimotoAbstract:OBJECTIVE: To examine association of 8 candidate genes with susceptibility to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japanese patients. Little is known on the genetic background of AAV in Japanese patients mainly because of the difficulty in collecting a sufficient number of samples for the genetics study. METHODS: Sixty-nine patients, including 50 with microscopic polyangiitis (MPA), were recruited in a multicenter study. Among them, 64 patients were positive for myeloperoxidase (MPO)-ANCA. Associations of HLA-DRB1, tumor necrosis factor-alpha promoter (TNF), TNF receptor 2 (TNFR2), Fcgamma receptor IIa (FCGR2A), IIb (FCGR2B), IIIa (FCGR3A), IIIb (FCGR3B), and CTLA-4 (CTLA4) polymorphisms were examined in a case-control analysis. RESULTS: A significant association of HLA-DRB1*0901 with MPA (p = 0.0037, OR 2.44, 95% CI 1.33-4.46), as well as with MPO-ANCA positivity (p = 0.0014, OR 2.44, 95% CI 1.41-4.22), was detected. There was no difference in the TNF promoter haplotype frequencies between patients with MPA and controls, excluding the possibility that the association of DRB1*0901 was secondarily caused by linkage disequilibrium with TNF. No association was observed for TNFR2, FCGR, or CTLA4 with MPA, nor with the presence of MPO-ANCA, although the combined genotype FCGR2A-131H/H and 3A-176F/F was increased in patients with MPA (p = 0.025). CONCLUSION: There was an association of HLA-DRB1*0901 with MPA and MPO-ANCA positive vasculitis in Japanese patients.
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Studies on the association of Fc gamma receptor IIA, IIB, IIIA and IIIB polymorphisms with rheumatoid arthritis in the Japanese: evidence for a genetic interaction between HLA-DRB1 and FCGR3A.
Genes and immunity, 2002Co-Authors: Chieko Kyogoku, Kunio Matsuta, Naoyuki Tsuchiya, Katsushi TokunagaAbstract:We recently detected a new single nucleotide polymorphism of FcgammaRIIB gene, which alters an amino acid within the transmembrane domain from Ile to Thr (I232T), and its association with SLE in the Japanese. This study was performed to examine whether FCGR2B-I232T was associated with susceptibility to rheumatoid arthritis in the Japanese. At the same time, FCGR2A, 3A and 3B polymorphisms were also examined. Genotyping of FCGR2B-I232T, FCGR2A-H131R, FCGR3A-F176V and FCGR3B-NA1/2 polymorphisms were performed using genomic DNA. Association with RA was analyzed in 382 Japanese patients with RA and 303 healthy individuals using a case-control approach. In addition, the same groups of patients and controls were genotyped for HLA-DRB1 to examine possible interaction with FCGR genes. Significantly different distribution of genotype, allele carrier and allele frequencies was not observed between patients with RA and healthy individuals in any of the four polymorphisms. When the subjects were stratified according to the carriage of HLA-DRB1 shared epitope (SE), significant increase of FCGR3A-176F/F genotype was observed in SE positive patients compared with SE positive healthy individuals (P=0.009, P(corr)=0.07). In conclusion, FCGR3A-176F/F genotype was considered to confer risk through genetic interaction with HLA-DRB1 SE.
Luminita Pricop - One of the best experts on this subject based on the ideXlab platform.
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the role of activating protein 1 in the transcriptional regulation of the human FCGR2B promoter mediated by the 343 g c polymorphism associated with systemic lupus erythematosus
Journal of Biological Chemistry, 2007Co-Authors: Mikhail Olferiev, Emi Masuda, Shizuko Tanaka, Marissa C. Blank, Luminita PricopAbstract:Abstract The inhibitory receptor FcγRIIb is a negative regulator of antibody production and inflammatory responses. The -343 G → C polymorphism in the human FCGR2B promoter is associated with systemic lupus erythematosus. The -343 C mutant promoter has decreased transcriptional activity. In the present study, we show that the transcriptional change correlates with quantitative differences in the interaction of the activating protein 1 complex with the mutant FCGR2B promoter. Promoter pulldown and chromatin immunoprecipitation assays demonstrated binding of c-Jun to the FCGR2B promoter. Phosphorylation of c-Jun was accompanied by transactivation of both FCGR2B promoter variants, whereas dephosphorylation of c-Jun by an inhibitor of c-Jun N-terminal kinase, markedly decreased the promoter activities. The -343 G → C substitution enabled the specific interaction of the transcription factor Yin-Yang 1 with the mutant FCGR2B promoter. Yin-Yang 1 competed with activating protein 1 for binding at the -343 site, and contributed to the repression of the mutant FCGR2B promoter activity. This mechanism could be responsible for the decreased expression of FcγRIIb associated with the -343 C/C homozygous FCGR2B genotype in lupus patients. These findings provide a rationale for the transcriptional defect mediated by the -343 C/C FCGR2B promoter polymorphism associated with systemic lupus erythematosus, and add to our understanding of the complex transcriptional regulation of the human FCGR2B promoter.
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The Role of Activating Protein 1 in the Transcriptional Regulation of the Human FCGR2B Promoter Mediated by the -343 G → C Polymorphism Associated with Systemic Lupus Erythematosus
The Journal of biological chemistry, 2006Co-Authors: Mikhail Olferiev, Emi Masuda, Shizuko Tanaka, Marissa C. Blank, Luminita PricopAbstract:Abstract The inhibitory receptor FcγRIIb is a negative regulator of antibody production and inflammatory responses. The -343 G → C polymorphism in the human FCGR2B promoter is associated with systemic lupus erythematosus. The -343 C mutant promoter has decreased transcriptional activity. In the present study, we show that the transcriptional change correlates with quantitative differences in the interaction of the activating protein 1 complex with the mutant FCGR2B promoter. Promoter pulldown and chromatin immunoprecipitation assays demonstrated binding of c-Jun to the FCGR2B promoter. Phosphorylation of c-Jun was accompanied by transactivation of both FCGR2B promoter variants, whereas dephosphorylation of c-Jun by an inhibitor of c-Jun N-terminal kinase, markedly decreased the promoter activities. The -343 G → C substitution enabled the specific interaction of the transcription factor Yin-Yang 1 with the mutant FCGR2B promoter. Yin-Yang 1 competed with activating protein 1 for binding at the -343 site, and contributed to the repression of the mutant FCGR2B promoter activity. This mechanism could be responsible for the decreased expression of FcγRIIb associated with the -343 C/C homozygous FCGR2B genotype in lupus patients. These findings provide a rationale for the transcriptional defect mediated by the -343 C/C FCGR2B promoter polymorphism associated with systemic lupus erythematosus, and add to our understanding of the complex transcriptional regulation of the human FCGR2B promoter.
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Decreased transcription of the human FCGR2B gene mediated by the -343 G/C promoter polymorphism and association with systemic lupus erythematosus
Human Genetics, 2005Co-Authors: Marissa C. Blank, Emi Masuda, Shizuko Tanaka, Radu N. Stefanescu, Francesc Marti, Philip D. King, Patricia Redecha, Robert J. Wurzburger, Margaret G. E. Peterson, Luminita PricopAbstract:The role for inhibitory Fc gamma receptors class IIb (FcγRIIb) in the onset, progression and severity of several animal models of autoimmune diseases is well established. By contrast, the pathogenic potential of FcγRIIb in human autoimmune diseases remains largely unknown. Here we report the identification of a polymorphism in the human FCGR2B promoter (dbSNP no. rs3219018) that is associated in homozygosity with systemic lupus erythematosus (SLE) phenotype in European-Americans (OR=11.1, P=0.003). Experimental evidence correlates the polymorphism (a G–C substitution at position –343 relative to the start of transcription) with altered FcγRIIb expression and function. The G–C substitution correlated with decreased transcription of the FCGR2B promoter, and resulted in decreased binding of the AP1 transcription complex to the mutant promoter sequence. The surface expression of FcγRIIb receptors was significantly reduced in activated B cells from (–343 C/C) SLE patients. These findings suggest that genetic defects may lead to deregulated expression of the FCGR2B gene in –343 C/C homozygous subjects, and may play a role in the pathogenesis of human SLE.
Katsushi Tokunaga - One of the best experts on this subject based on the ideXlab platform.
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Human CD72 splicing isoform responsible for resistance to systemic lupus erythematosus regulates serum immunoglobulin level and is localized in endoplasmic reticulum
BMC immunology, 2012Co-Authors: Yuki Hitomi, Takahiro Adachi, Naoyuki Tsuchiya, Zen-ichiro Honda, Katsushi Tokunaga, Takeshi TsubataAbstract:Background CD72 is an inhibitory co-receptor expressed on B cells. We previously demonstrated significant association of the polymorphism of the CD72 gene with susceptibility to human systemic lupus erythematosus (SLE) in individuals carrying a SLE-susceptible FCGR2B genotype (FCGR2B-232Thr/Thr). The human CD72 locus generates a splicing isoform that lacks exon 8 (CD72Δex8) as well as full-length CD72 (CD72fl), and the CD72 polymorphism regulates exon 8 skipping.
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Role of B cell inhibitory receptor polymorphisms in systemic lupus erythematosus: a negative times a negative makes a positive
Journal of Human Genetics, 2006Co-Authors: Naoyuki Tsuchiya, Zen-ichiro Honda, Katsushi TokunagaAbstract:B lymphocytes play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). Here, we will review our studies on the role of polymorphisms of two genes coding for B cell inhibitory receptors, FCGR2B and CD72 . In FCGR2B , a single nucleotide polymorphism leading to a nonsynonymous substitution, Ile232Thr, within the transmembrane domain was identified, and a significant association of the 232Thr/Thr genotype with SLE was observed in Japanese, Thai and Chinese populations, while this allele was found to be rare in Caucasians. On the other hand, the association of FCGR2B promoter polymorphism with SLE in Caucasians has been reported by two independent groups, but this allele was not found to be present in Japanese. These observations demonstrate that the association of FCGR2B polymorphisms with SLE is common to multiple populations, but the alleles associated with SLE depend upon the genetic background of each population. Functional analyses using a human B cell line lacking endogenous FcγRIIb revealed that SLE-associated 232Thr allele product was partially excluded from membrane lipid rafts under resting conditions and after coligation with B cell receptor, and was significantly less potent at inhibiting B cell activation. Two haplotypes were identified in CD72 , one of which was associated with increased production of an alternative splicing isoform that substantially alters the extracellular region of CD72. Interestingly, the presence of the haplotype significantly decreased the risk of SLE conferred by FCGR2B -232Thr in an epistatic manner. These observations emphasize the need to understand human immune system diversity if we are to improve our understanding of the pathogenesis of autoimmune diseases.
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Association of Fcγ receptor IIb polymorphism with susceptibility to systemic lupus erythematosus in Chinese: a common susceptibility gene in the Asian populations
Tissue antigens, 2004Co-Authors: Z.t. Chu, Chieko Kyogoku, Naoyuki Tsuchiya, Jun Ohashi, Ya-ping Qian, C.z. Mao, J. Y. Chu, Katsushi TokunagaAbstract:The association of Fcgamma receptor (FcgammaR) polymorphisms with systemic lupus erythematosus (SLE) has been demonstrated in various populations; however, the results have been inconsistent. We recently identified a single-nucleotide polymorphism encoding a non-synonymous substitution, Ile232Thr (I232T), of FCGR2B and its association with SLE in Japanese and in Thais. Multiple functional FcgammaR genes with polymorphisms (FCGR2A, FCGR2B, FCGR3A, and FCGR3B) cluster in 1q23, and some of them are in linkage disequilibrium (LD). To differentiate contributions from multiple-linked loci, comparison of different populations may provide useful information. In this study, we analyzed the above four FCGR polymorphisms of the Chinese patients and controls for the association with SLE. FCGR2A-H131R, FCGR2B-I232T, FCGR3A-F176V, and FCGR3B genotypes were determined in 167 Chinese patients with SLE and 129 healthy controls. Association was examined using case-control analysis. Allele frequencies of FCGR2B-232T and FCGR3A-176F were significantly increased in SLE [odds ratio (OR) = 1.67 and OR = 1.41, respectively]. Interestingly, while these alleles had a tendency of positive LD in the controls, FCGR2B-232T was in positive association with FCGR3A-176V in SLE, suggesting that these two alleles were associated with SLE in an independent manner. Comparison between SLE with and without nephritis indicated significant association of FCGR2B-232T with nephritis (OR = 2.65). When the present results were combined with our previous data on the Japanese and the Thais using meta-analytic methods, highly significant and independent association was observed for FCGR2B and FCGR3A genotypes. These results strongly suggested that FCGR2B is a common susceptibility factor to SLE in the Asians.
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genetic background of japanese patients with antineutrophil cytoplasmic antibody associated vasculitis association of hla drb1 0901 with microscopic polyangiitis
The Journal of Rheumatology, 2003Co-Authors: Naoyuki Tsuchiya, Chieko Kyogoku, Katsushi Tokunaga, Aya Kawasaki, Shigeto Kobayashi, Yoshihiro Arimura, Masaharu Yoshida, Hiroshi HashimotoAbstract:OBJECTIVE: To examine association of 8 candidate genes with susceptibility to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japanese patients. Little is known on the genetic background of AAV in Japanese patients mainly because of the difficulty in collecting a sufficient number of samples for the genetics study. METHODS: Sixty-nine patients, including 50 with microscopic polyangiitis (MPA), were recruited in a multicenter study. Among them, 64 patients were positive for myeloperoxidase (MPO)-ANCA. Associations of HLA-DRB1, tumor necrosis factor-alpha promoter (TNF), TNF receptor 2 (TNFR2), Fcgamma receptor IIa (FCGR2A), IIb (FCGR2B), IIIa (FCGR3A), IIIb (FCGR3B), and CTLA-4 (CTLA4) polymorphisms were examined in a case-control analysis. RESULTS: A significant association of HLA-DRB1*0901 with MPA (p = 0.0037, OR 2.44, 95% CI 1.33-4.46), as well as with MPO-ANCA positivity (p = 0.0014, OR 2.44, 95% CI 1.41-4.22), was detected. There was no difference in the TNF promoter haplotype frequencies between patients with MPA and controls, excluding the possibility that the association of DRB1*0901 was secondarily caused by linkage disequilibrium with TNF. No association was observed for TNFR2, FCGR, or CTLA4 with MPA, nor with the presence of MPO-ANCA, although the combined genotype FCGR2A-131H/H and 3A-176F/F was increased in patients with MPA (p = 0.025). CONCLUSION: There was an association of HLA-DRB1*0901 with MPA and MPO-ANCA positive vasculitis in Japanese patients.
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Studies on the association of Fc gamma receptor IIA, IIB, IIIA and IIIB polymorphisms with rheumatoid arthritis in the Japanese: evidence for a genetic interaction between HLA-DRB1 and FCGR3A.
Genes and immunity, 2002Co-Authors: Chieko Kyogoku, Kunio Matsuta, Naoyuki Tsuchiya, Katsushi TokunagaAbstract:We recently detected a new single nucleotide polymorphism of FcgammaRIIB gene, which alters an amino acid within the transmembrane domain from Ile to Thr (I232T), and its association with SLE in the Japanese. This study was performed to examine whether FCGR2B-I232T was associated with susceptibility to rheumatoid arthritis in the Japanese. At the same time, FCGR2A, 3A and 3B polymorphisms were also examined. Genotyping of FCGR2B-I232T, FCGR2A-H131R, FCGR3A-F176V and FCGR3B-NA1/2 polymorphisms were performed using genomic DNA. Association with RA was analyzed in 382 Japanese patients with RA and 303 healthy individuals using a case-control approach. In addition, the same groups of patients and controls were genotyped for HLA-DRB1 to examine possible interaction with FCGR genes. Significantly different distribution of genotype, allele carrier and allele frequencies was not observed between patients with RA and healthy individuals in any of the four polymorphisms. When the subjects were stratified according to the carriage of HLA-DRB1 shared epitope (SE), significant increase of FCGR3A-176F/F genotype was observed in SE positive patients compared with SE positive healthy individuals (P=0.009, P(corr)=0.07). In conclusion, FCGR3A-176F/F genotype was considered to confer risk through genetic interaction with HLA-DRB1 SE.
V. Fonollosa - One of the best experts on this subject based on the ideXlab platform.
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evidence that deletion at fcgr3b is a risk factor for systemic sclerosis
Genes and Immunity, 2012Co-Authors: Cushla Mckinney, J Broen, Lorenzo Beretta, Roger Hesselstrand, Madelon C Vonk, Nico Hunzelmann, Carmen P. Simeon, Gabriela Riemekasten, Ralph Scorza, V. FonollosaAbstract:There is increasing evidence that gene copy number (CN) variation influences clinical phenotype. The low-affinity Fc receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment of polymorphonuclear neutrophils to sites of inflammation and their activation. Given the genetic overlap between systemic lupus erythematosus and systemic sclerosis (SSc) and the strong evidence for FCGR3B CN in the pathology of SLE, we hypothesised that FCGR3B gene dosage influences susceptibility to SSc. We obtained FCGR3B deletion status in 777 European Caucasian cases and 1000 controls. There was an inverse relationship between FCGR3B CN and disease susceptibility. CN of = 2. Although requiring replication, these results suggest that impaired immune complex clearance arising from FCGR3B deficiency contributes to the pathology of SSc, and FCGR3B CN variation is a common risk factor for systemic autoimmunity. (Less)
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Evidence that deletion at FCGR3B is a risk factor for systemic sclerosis
Genes & Immunity, 2012Co-Authors: Cushla Mckinney, J Broen, Lorenzo Beretta, Roger Hesselstrand, Madelon C Vonk, Nico Hunzelmann, Carmen P. Simeon, Gabriela Riemekasten, Ralph Scorza, V. FonollosaAbstract:There is increasing evidence that gene copy number (CN) variation influences clinical phenotype. The low-affinity Fc receptor 3B ( FCGR3B ) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment of polymorphonuclear neutrophils to sites of inflammation and their activation. Given the genetic overlap between systemic lupus erythematosus and systemic sclerosis (SSc) and the strong evidence for FCGR3B CN in the pathology of SLE, we hypothesised that FCGR3B gene dosage influences susceptibility to SSc. We obtained FCGR3B deletion status in 777 European Caucasian cases and 1000 controls. There was an inverse relationship between FCGR3B CN and disease susceptibility. CN of ⩽1 was a significant risk factor for SSc (OR=1.55 (1.13–2.14), P =0.007) relative to CN⩾2. Although requiring replication, these results suggest that impaired immune complex clearance arising from FCGR3B deficiency contributes to the pathology of SSc, and FCGR3B CN variation is a common risk factor for systemic autoimmunity.
