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Gwan Gyu Song - One of the best experts on this subject based on the ideXlab platform.
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associations between functional fcgr2a r131h and FCGR3A f158v polymorphisms and responsiveness to tnf blockers in spondyloarthropathy psoriasis and crohn s disease a meta analysis
Pharmacogenomics, 2016Co-Authors: Young Ho Lee, Sung Jae Choi, Gwan Gyu SongAbstract:Aim: The aim of the current study was to investigate whether FCGR polymorphisms are associated with responsiveness to anti-TNF-α therapy in patients with spondyloarthropathy, psoriasis, and Crohn's disease. Materials & methods: We conducted a meta-analysis to evaluate the association between the functional FCGR3A F158V and FCGR2A R131H polymorphisms and responsiveness to TNF blockers. Results: The meta-analysis indicated that responsiveness to TNF blockers was associated with the FCGR3A V allele (odds ratio: 3.308; 95% CI: 1.053–10.39; p = 0.040) and the FCGR2A RR + RH genotype (odds ratio: 3.904; p = 0.027) in patients with a follow-up time of ≥6 months. Conclusion: FCGR3A V and FCGR2A R allele carriers show better responsiveness to anti-TNF-α therapy in patients with follow-up times ≥6 months.
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fcgr2a FCGR3A fcgr3b polymorphisms and susceptibility to rheumatoid arthritis a meta analysis
Clinical and Experimental Rheumatology, 2015Co-Authors: Gwan Gyu SongAbstract:Abstract The aim of this study is to explore whether Fc gamma receptor (FCGR) polymorphisms are associated with the susceptibility to rheumatoid arthritis (RA). We conducted a meta-analysis on the association between FCGR2A H131R (rs1801274), FCGR3A F158V (rs396991), and FCGR3B NA1/NA2 polymorphisms and RA susceptibility. A total of seventeen studies reported in fourteen articles (4,418 patients with RA and 3,560 controls) were considered in our meta-analysis. In all of the study subjects, meta-analysis indicated an association between RA and FCGR2A R allele (OR=0.877, 95% CI=0.792-0.971, p=0.011). Stratification by ethnicity indicated an association between FCGR2A R allele and RA in Europeans (OR=0.816, 95% CI=0.687-0.968, p=0.020), but not in East Asians (OR=0.900, 95% CI=0.778-1.040, p=0.154). Meta-analysis revealed an association between RA and FCGR3A VV vs. FF genotype in all the study subjects (OR=1.210, 95% CI=1.067-1.479, p=0.006). Stratification by ethnicity indicated an association between FCGR3A VV genotype and RA compared toFF genotype in Europeans (OR=1.350, 95% CI=1.107-1.646, p=0.003), but not in East Asians and South Asians. No association was observed between RA and FCGR3B polymorphisms on performing the meta-analysis. Although no relationship was found between the FCGR3B polymorphism and RA susceptibility, FCGR2A and FCGR3A polymorphisms were found to be associated with RA in Europeans, but not in Asians.
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fcgr2a FCGR3A fcgr3b polymorphisms and susceptibility to rheumatoid arthritis a meta analysis
Clinical and Experimental Rheumatology, 2015Co-Authors: Young Ho Lee, Sang Cheol Bae, Gwan Gyu SongAbstract:OBJECTIVES The aim of this study is to explore whether Fc gamma receptor (FCGR) polymorphisms are associated with the susceptibility to rheumatoid arthritis (RA). METHODS We conducted a meta-analysis on the association between FCGR2A H131R (rs1801274), FCGR3A F158V (rs396991), and FCGR3B NA1/NA2 polymorphisms and RA susceptibility. RESULTS A total of seventeen studies reported in fourteen articles (4,418 patients with RA and 3,560 controls) were considered in our meta-analysis. In all of the study subjects, meta-analysis indicated an association between RA and FCGR2A R allele (OR=0.877, 95% CI=0.792-0.971, p=0.011). Stratification by ethnicity indicated an association between FCGR2A R allele and RA in Europeans (OR=0.816, 95% CI=0.687-0.968, p=0.020), but not in East Asians (OR=0.900, 95% CI=0.778-1.040, p=0.154). Meta-analysis revealed an association between RA and FCGR3A VV vs. FF genotype in all the study subjects (OR=1.210, 95% CI=1.067-1.479, p=0.006). Stratification by ethnicity indicated an association between FCGR3A VV genotype and RA compared toFF genotype in Europeans (OR=1.350, 95% CI=1.107-1.646, p=0.003), but not in East Asians and South Asians. No association was observed between RA and FCGR3B polymorphisms on performing the meta-analysis. CONCLUSIONS Although no relationship was found between the FCGR3B polymorphism and RA susceptibility, FCGR2A and FCGR3A polymorphisms were found to be associated with RA in Europeans, but not in Asians.
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functional FCGR3A 158 v f and il 6 174 c g polymorphisms predict response to biologic therapy in patients with rheumatoid arthritis a meta analysis
Rheumatology International, 2014Co-Authors: Young Ho Lee, Sang Cheol Bae, Gwan Gyu SongAbstract:The aim of this study was to investigate whether the Fc gamma receptor 3A (FCGR3A) 158 V/F and interleukin-6 (IL-6) promoter −174 G/C polymorphisms can predict the response to biologic-based therapy in patients with rheumatoid arthritis (RA). We conducted a meta-analysis of studies on the association between the FCGR3A V/F polymorphism or the IL-6 −174 C/G polymorphism and non-responsiveness to biologic therapy in RA patients. A total of 10 studies involving 1,427 patients were considered. These studies consisted of seven studies on the FCGR3A polymorphism and three studies on the IL-6 polymorphism. Meta-analysis showed no association between the FCGR3A VV+VF genotype and non-responders to biologic therapy [odds ratio (OR) 0.881, 95 % confidence interval (CI) 0.505–1.537, p = 0.655]. However, stratification by biologic type indicated an association between the FCGR3A VV+VF genotype and non-responders to rituximab (OR 0.566, 95 % CI 0.373–0.857, p = 0.007), but no association was found in non-responders to tumor necrosis factor (TNF)-blockers (OR 1.337, 95 % CI 0.869–2.056, p = 0.186). Meta-analysis revealed no association between the IL-6 CC+CG genotype and non-responders to the biologics (OR 3.233, 95 % CI 0.766–13.64, p = 0.110). However, an association was found between the IL-6 CC+CG genotype and non-responders to anti-TNF therapy (OR 8.030, 95 % CI 1.807–33.68, p = 0.006). This meta-analysis demonstrates that FCGR3A V allele carriers show a better response to rituximab, and individuals carrying the IL-6 −174 C allele show a poorer response to anti-TNF therapy for RA. Genotyping for these polymorphisms may be a useful tool for predicting the response to biologics with respect to personalized medicine.
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associations between fcgr2a rs1801274 FCGR3A rs396991 fcgr3b na1 na2 polymorphisms and periodontitis a meta analysis
Molecular Biology Reports, 2013Co-Authors: Gwan Gyu SongAbstract:The aim of this study was to determine whether the Fcγ receptors (FCGRs) polymorphisms confer susceptibility to periodontitis in ethnically different populations. We did a literature search using PubMed and Embase, and conducted a meta-analysis on the associations between the FCGR2A H131R (rs1801274), FCGR3A F158V (rs396991), and FCGR3B NA1/NA2 polymorphisms and periodontitis using allele contrast, the recessive model, the dominant model, and the homozygote contrast. A total of 17 separate comparisons with 1,421 patients with periodontitis and 1,454 controls, involving six Caucasian, six East Asian, two African and one South Asian population were considered in the meta-analysis. Meta-analysis of the FCGR2A H131R polymorphism showed no association between periodontitis and the FCGR2A R allele (OR = 0.987, 95 % CI = 0.881–1.107, p = 0.827). Stratification by ethnicity revealed an association between the RR+RH genotype with periodontitis in Caucasian population (OR = 0.624, 95 % CI = 0.479–0.813, p = 4.7 × 10−5), but not in East Asian, and African populations. Meta-analysis of the FCGR3A F158V polymorphism revealed an association between the FCGR3A V allele and periodontitis is in Caucasians (OR = 1.457, 95 % CI = 1.014–2.092, p = 0.042), but not in East Asians and Africans. In addition, analysis using the dominant model and homozygote contrast showed the same pattern for the FCGR3A V allele. Meta-analysis of the FCGR3B NA1/NA2 polymorphism using the recessive model revealed a significant association between the NA2/NA2 genotype and periodontitis in aggressive periodontitis (OR = 2.853, 95 % CI = 1.673–4.863, 1.1 × 10−5). This meta-analysis demonstrates that the FCGR2A, and FCGR3A polymorphisms may confer susceptibility to periodontitis in Caucasians, and that the FCGR3B polymorphism may be associated with susceptibility to aggressive periodontitis.
John D. Isaacs - One of the best experts on this subject based on the ideXlab platform.
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confirmation of association of fcgr3b but not FCGR3A copy number with susceptibility to autoantibody positive rheumatoid arthritis
Human Mutation, 2012Co-Authors: J. Robinson, Lubna Haroon Rashid, Stephen G. Martin, Anne Barton, Anthony G Wilson, John D. Isaacs, Ian M. Carr, Paul Emery, D. Cooper, Jennifer H BarrettAbstract:The FCGR locus encoding the low-affinity Fc? receptors for IgG has largely been missed by genome-wide association studies due to complications with structural variation and segmental duplication. Recently identified CNVs affecting FCGR3A and FCGR3B have been linked to a number of autoimmune disorders. We have developed and validated a novel quantitative sequence variant (QSV) assay in combination with an adapted paralogue ratio test to examine independent CNVs carrying FCGR3A and FCGR3B in rheumatoid arthritis (RA) compared with healthy controls (n=1115 and 654, respectively). Implementation of a robust statistical analysis framework (CNVtools) allowed for systematic batch effects and for the inherent uncertainty of copy number assignment, thus avoiding two major sources of false positive results. Evidence for association with neither duplications nor deletions of FCGR3A was found, however, in line with previous studies there was evidence of overrepresentation of FCGR3B deletions in RA (OR 1.50, P=0.028), which was more apparent in rheumatoid factor positive disease (OR 1.61, P=0.011). The level of Fc?RIIIb, encoded by FCGR3B, expression on neutrophils was shown to correlate with gene copy number. Thus, our results may highlight an important role for neutrophils in the pathogenesis of RA, potentially through reduced Fc?RIIIb-mediated immune-complex clearance.
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confirmation of association of fcgr3b but not FCGR3A copy number with susceptibility to autoantibody positive rheumatoid arthritis
Human Mutation, 2012Co-Authors: Jim I Robinson, Lubna Haroon Rashid, Stephen G. Martin, Anne Barton, Anthony G Wilson, John D. Isaacs, Ian M. Carr, Paul Emery, Dawn L Cooper, Jennifer H BarrettAbstract:The FCGR locus encoding the low-affinity Fcγ receptors (FcγR) for immunoglobulin G has largely been missed by genome-wide association studies due to complications with structural variation and segmental duplication. Recently identified copy number variants (CNVs) affecting FCGR3A and FCGR3B have been linked to a number of autoimmune disorders. We have developed and validated a novel quantitative sequence variant assay in combination with an adapted paralogue ratio test to examine independent CNVs carrying FCGR3A and FCGR3B in rheumatoid arthritis (RA) compared with healthy volunteers (n = 1,115 and 654, respectively). Implementation of a robust statistical analysis framework (CNVtools) allowed for systematic batch effects and for the inherent uncertainty of copy number assignment, thus avoiding two major sources of false positive results. Evidence for association with neither duplications nor deletions of FCGR3A was found; however, in line with previous studies, there was evidence of overrepresentation of FCGR3B deletions in RA (odds ratio [OR] 1.50, P = 0.028), which was more apparent in rheumatoid factor positive disease (OR 1.61, P = 0.011). The level of FcγRIIIb, encoded by FCGR3B, expression on neutrophils was shown to correlate with gene copy number. Thus, our results may highlight an important role for neutrophils in the pathogenesis of RA, potentially through reduced FcγRIIIb-mediated immune complex clearance.
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dissection of the FCGR3A association with ra increased association in men and with autoantibody positive disease
Annals of the Rheumatic Diseases, 2010Co-Authors: Jim I Robinson, Jennifer H Barrett, Anne Barton, Anthony G Wilson, John D. Isaacs, Paul Emery, John C Taylor, Marc Naven, D Corscadden, Ann W MorganAbstract:Objectives Genome-wide association studies in rheumatoid arthritis (RA) have failed to examine the FCGR gene cluster because of the confounding effects of segmental duplication. This study aimed to replicate previous candidate gene studies that had identified a significant association between the FCGR3A -158V allele and RA and then sought to estimate specific subgroup effects. Methods FCGR3A -158F/V genotyping was undertaken in a UK Caucasian replication cohort comprising 2049 patients with RA and 1156 controls. Subgroup analyses assessing the magnitude of association according to gender and autoantibody (rheumatoid factor (RF) and cyclic citrullinated peptide (CCP)) status were undertaken in a pooled cohort of 2963 patients with RA and 1731 controls. Logistic regression was used to test for interaction between FCGR3A and HLA-DRB1 shared epitope (SE) alleles. Results In the combined RA cohort, borderline association with homozygosity was found for the FCGR3A -158V allele (OR 1.2, p=0.05), which was stronger in men (OR 1.7, p=0.01). Stratification by autoantibody status showed an increased risk in RF and CCP positive RA. Analysis of the FCGR3A-158V and HLA-DRB1 SE interaction revealed roles for both genes in susceptibility to autoantibody positive RA, with no evidence of interaction. Conclusions FCGR3A is a risk factor for the development of autoantibody positive RA, particularly in men, with evidence of a multiplicative effect with HLA-DRB1 SE.
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association of fcgr2a and fcgr2a FCGR3A haplotypes with susceptibility to giant cell arteritis
Arthritis Research & Therapy, 2006Co-Authors: Ann W Morgan, Jennifer H Barrett, Jim I Robinson, John D. Isaacs, Javier Martin, Amy Walker, Sarah J Babbage, William E R Ollier, Miguel A GonzalezgayAbstract:The Fc gamma receptors have been shown to play important roles in the initiation and regulation of many immunological and inflammatory processes and to amplify and refine the immune response to an infection. We have investigated the hypothesis that polymorphism within the FCGR genetic locus is associated with giant cell arteritis (GCA). Biallelic polymorphisms in FCGR2A, FCGR3A, FCGR3B and FCGR2B were examined for association with biopsy-proven GCA (n = 85) and healthy ethnically matched controls (n = 132) in a well-characterised cohort from Lugo, Spain. Haplotype frequencies and linkage disequilibrium (D') were estimated across the FCGR locus and a model-free analysis performed to determine association with GCA. There was a significant association between FCGR2A-131RR homozygosity (odds ratio (OR) 2.10, 95% confidence interval (CI) 1.12 to 3.77, P = 0.02, compared with all others) and carriage of FCGR3A-158F (OR 3.09, 95% CI 1.10 to 8.64, P = 0.03, compared with non-carriers) with susceptibility to GCA. FCGR haplotypes were examined to refine the extent of the association. The haplotype showing the strongest association with GCA susceptibility was the FCGR2A-FCGR3A 131R-158F haplotype (OR 2.84, P = 0.01 for homozygotes compared with all others). There was evidence of a multiplicative joint effect between homozygosity for FCGR2A-131R and HLA-DRB1*04 positivity, consistent with both of these two genetic factors contributing to the risk of disease. The risk of GCA in HLA-DRB1*04 positive individuals homozygous for the FCGR2A-131R allele is increased almost six-fold compared with those with other FCGR2A genotypes who are HLA-DRB1*04 negative. We have demonstrated that FCGR2A may contribute to the 'susceptibility' of GCA in this Spanish population. The increased association observed with a FCGR2A-FCGR3A haplotype suggests the presence of additional genetic polymorphisms in linkage disequilibrium with this haplotype that may contribute to disease susceptibility. These findings may ultimately provide new insights into disease pathogenesis.
Francoise Dignatgeorge - One of the best experts on this subject based on the ideXlab platform.
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FCGR3A and fcgr2a genotypes differentially impact allograft rejection and patients survival after lung transplant
Frontiers in Immunology, 2019Co-Authors: Pascale Paul, Pascal Pedini, Luc Lyonnet, Julie Di Cristofaro, Anderson Loundou, Mathieu Pelardy, Agnes Basire, Francoise DignatgeorgeAbstract:Fc gamma receptors (FcγRs) play a major role in the regulation of humoral immune responses. Single-nucleotide polymorphisms (SNPs) of FCGR2A and FCGR3A can impact the expression level, IgG affinity and function of the CD32 and CD16 FcγRs in response to their engagement by the Fc fragment of IgG. The CD16 isoform encoded by FCGR3A [158V/V] controls the intensity of antibody-dependent cytotoxic alloimmune responses of natural killer cells (NK) and has been identified as a susceptibility marker predisposing patients to cardiac allograft vasculopathy after heart transplant. This study aimed to investigate whether FCGR2A and FCGR3A polymorphisms can also be associated with the clinical outcome of lung transplant recipients (LTRs). The SNPs of FCGR2A ([131R/H], rs1801274) and FCGR3A ([158V/F], rs396991) were identified in 158 LTx recipients (LTR) and 184 Controls (CTL). The corresponding distribution of genotypic and allelic combinations was analyzed for potential links with the development of circulating donor-specific anti-HLA alloantibodies (DSA) detected at months 1 and 3 after lung transplant (LTx), the occurrence of acute rejection (AR) and chronic lung allograft dysfunction (CLAD), and the overall survival of LTRs. The FCGR3A [158V/V] genotype was identified as an independent susceptibility factor associated with higher rates of AR during the first trimester after LTx (HR 4.8, p<0.0001, 95% CI 2.37-9.61), but it could not be associated with the level of CD16- mediated NK cell activation in response to the LTR’s DSA, whatever the MFI intensity and C1q binding profiles of the DSA evaluated. The FCGR2A [131R/R] genotype was associated with lower CLAD-free survival of LTRs, independently of the presence of DSA at 3 months (HR 1.8, p=0.024, 95% CI 1.08-3.03). Our data indicate that FCGR SNPs differentially affect the clinical outcome of LTRs and may be of use to stratify patients at higher risk of experiencing graft rejection. Furthermore, these data suggest that in the LTx setting, specific mechanisms of humoral alloreactivity, which cannot be solely explained by the complement and CD16-mediated pathogenic effects of DSA, may be involved in the development of acute and chronic lung allograft rejection.
Alexander Dobrovic - One of the best experts on this subject based on the ideXlab platform.
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a critical review of the role of fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer
Journal of Hematology & Oncology, 2013Co-Authors: James D Mellor, Michael P Brown, Helen Irving, John Zalcberg, Alexander DobrovicAbstract:Antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism of action of therapeutic monoclonal antibodies (mAbs) such as cetuximab, rituximab and trastuzumab. Fc gamma receptors (FcgR) on human white blood cells are an integral part of the ADCC pathway. Differential response to therapeutic mAbs has been reported to correlate with specific polymorphisms in two of these genes: FCGR2A (H131R) and FCGR3A (V158F). These polymorphisms are associated with differential affinity of the receptors for mAbs. This review critically examines the current evidence for genotyping the corresponding single nucleotide polymorphisms (SNPs) to predict response to mAbs in patients with cancer.
Jennifer H Barrett - One of the best experts on this subject based on the ideXlab platform.
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confirmation of association of fcgr3b but not FCGR3A copy number with susceptibility to autoantibody positive rheumatoid arthritis
Human Mutation, 2012Co-Authors: J. Robinson, Lubna Haroon Rashid, Stephen G. Martin, Anne Barton, Anthony G Wilson, John D. Isaacs, Ian M. Carr, Paul Emery, D. Cooper, Jennifer H BarrettAbstract:The FCGR locus encoding the low-affinity Fc? receptors for IgG has largely been missed by genome-wide association studies due to complications with structural variation and segmental duplication. Recently identified CNVs affecting FCGR3A and FCGR3B have been linked to a number of autoimmune disorders. We have developed and validated a novel quantitative sequence variant (QSV) assay in combination with an adapted paralogue ratio test to examine independent CNVs carrying FCGR3A and FCGR3B in rheumatoid arthritis (RA) compared with healthy controls (n=1115 and 654, respectively). Implementation of a robust statistical analysis framework (CNVtools) allowed for systematic batch effects and for the inherent uncertainty of copy number assignment, thus avoiding two major sources of false positive results. Evidence for association with neither duplications nor deletions of FCGR3A was found, however, in line with previous studies there was evidence of overrepresentation of FCGR3B deletions in RA (OR 1.50, P=0.028), which was more apparent in rheumatoid factor positive disease (OR 1.61, P=0.011). The level of Fc?RIIIb, encoded by FCGR3B, expression on neutrophils was shown to correlate with gene copy number. Thus, our results may highlight an important role for neutrophils in the pathogenesis of RA, potentially through reduced Fc?RIIIb-mediated immune-complex clearance.
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confirmation of association of fcgr3b but not FCGR3A copy number with susceptibility to autoantibody positive rheumatoid arthritis
Human Mutation, 2012Co-Authors: Jim I Robinson, Lubna Haroon Rashid, Stephen G. Martin, Anne Barton, Anthony G Wilson, John D. Isaacs, Ian M. Carr, Paul Emery, Dawn L Cooper, Jennifer H BarrettAbstract:The FCGR locus encoding the low-affinity Fcγ receptors (FcγR) for immunoglobulin G has largely been missed by genome-wide association studies due to complications with structural variation and segmental duplication. Recently identified copy number variants (CNVs) affecting FCGR3A and FCGR3B have been linked to a number of autoimmune disorders. We have developed and validated a novel quantitative sequence variant assay in combination with an adapted paralogue ratio test to examine independent CNVs carrying FCGR3A and FCGR3B in rheumatoid arthritis (RA) compared with healthy volunteers (n = 1,115 and 654, respectively). Implementation of a robust statistical analysis framework (CNVtools) allowed for systematic batch effects and for the inherent uncertainty of copy number assignment, thus avoiding two major sources of false positive results. Evidence for association with neither duplications nor deletions of FCGR3A was found; however, in line with previous studies, there was evidence of overrepresentation of FCGR3B deletions in RA (odds ratio [OR] 1.50, P = 0.028), which was more apparent in rheumatoid factor positive disease (OR 1.61, P = 0.011). The level of FcγRIIIb, encoded by FCGR3B, expression on neutrophils was shown to correlate with gene copy number. Thus, our results may highlight an important role for neutrophils in the pathogenesis of RA, potentially through reduced FcγRIIIb-mediated immune complex clearance.
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dissection of the FCGR3A association with ra increased association in men and with autoantibody positive disease
Annals of the Rheumatic Diseases, 2010Co-Authors: Jim I Robinson, Jennifer H Barrett, Anne Barton, Anthony G Wilson, John D. Isaacs, Paul Emery, John C Taylor, Marc Naven, D Corscadden, Ann W MorganAbstract:Objectives Genome-wide association studies in rheumatoid arthritis (RA) have failed to examine the FCGR gene cluster because of the confounding effects of segmental duplication. This study aimed to replicate previous candidate gene studies that had identified a significant association between the FCGR3A -158V allele and RA and then sought to estimate specific subgroup effects. Methods FCGR3A -158F/V genotyping was undertaken in a UK Caucasian replication cohort comprising 2049 patients with RA and 1156 controls. Subgroup analyses assessing the magnitude of association according to gender and autoantibody (rheumatoid factor (RF) and cyclic citrullinated peptide (CCP)) status were undertaken in a pooled cohort of 2963 patients with RA and 1731 controls. Logistic regression was used to test for interaction between FCGR3A and HLA-DRB1 shared epitope (SE) alleles. Results In the combined RA cohort, borderline association with homozygosity was found for the FCGR3A -158V allele (OR 1.2, p=0.05), which was stronger in men (OR 1.7, p=0.01). Stratification by autoantibody status showed an increased risk in RF and CCP positive RA. Analysis of the FCGR3A-158V and HLA-DRB1 SE interaction revealed roles for both genes in susceptibility to autoantibody positive RA, with no evidence of interaction. Conclusions FCGR3A is a risk factor for the development of autoantibody positive RA, particularly in men, with evidence of a multiplicative effect with HLA-DRB1 SE.
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association of fcgr2a and fcgr2a FCGR3A haplotypes with susceptibility to giant cell arteritis
Arthritis Research & Therapy, 2006Co-Authors: Ann W Morgan, Jennifer H Barrett, Jim I Robinson, John D. Isaacs, Javier Martin, Amy Walker, Sarah J Babbage, William E R Ollier, Miguel A GonzalezgayAbstract:The Fc gamma receptors have been shown to play important roles in the initiation and regulation of many immunological and inflammatory processes and to amplify and refine the immune response to an infection. We have investigated the hypothesis that polymorphism within the FCGR genetic locus is associated with giant cell arteritis (GCA). Biallelic polymorphisms in FCGR2A, FCGR3A, FCGR3B and FCGR2B were examined for association with biopsy-proven GCA (n = 85) and healthy ethnically matched controls (n = 132) in a well-characterised cohort from Lugo, Spain. Haplotype frequencies and linkage disequilibrium (D') were estimated across the FCGR locus and a model-free analysis performed to determine association with GCA. There was a significant association between FCGR2A-131RR homozygosity (odds ratio (OR) 2.10, 95% confidence interval (CI) 1.12 to 3.77, P = 0.02, compared with all others) and carriage of FCGR3A-158F (OR 3.09, 95% CI 1.10 to 8.64, P = 0.03, compared with non-carriers) with susceptibility to GCA. FCGR haplotypes were examined to refine the extent of the association. The haplotype showing the strongest association with GCA susceptibility was the FCGR2A-FCGR3A 131R-158F haplotype (OR 2.84, P = 0.01 for homozygotes compared with all others). There was evidence of a multiplicative joint effect between homozygosity for FCGR2A-131R and HLA-DRB1*04 positivity, consistent with both of these two genetic factors contributing to the risk of disease. The risk of GCA in HLA-DRB1*04 positive individuals homozygous for the FCGR2A-131R allele is increased almost six-fold compared with those with other FCGR2A genotypes who are HLA-DRB1*04 negative. We have demonstrated that FCGR2A may contribute to the 'susceptibility' of GCA in this Spanish population. The increased association observed with a FCGR2A-FCGR3A haplotype suggests the presence of additional genetic polymorphisms in linkage disequilibrium with this haplotype that may contribute to disease susceptibility. These findings may ultimately provide new insights into disease pathogenesis.
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Analysis of Fcγ receptor haplotypes in rheumatoid arthritis: FCGR3A remains a major susceptibility gene at this locus, with an additional contribution from FCGR3B
Arthritis Research & Therapy, 2005Co-Authors: Ann W Morgan, Jennifer H Barrett, Bridget Griffiths, Jim I Robinson, Viki H Keyte, Arthur W Boylston, Deepak Subramanian, Elizabeth A. Jones, Frederique Ponchel, R Deva SitunayakeAbstract:The Fcγ receptors play important roles in the initiation and regulation of many immunological and inflammatory processes, and genetic variants ( FCGR ) have been associated with numerous autoimmune and infectious diseases. The data in rheumatoid arthritis (RA) are conflicting and we previously demonstrated an association between FCGR3A and RA. In view of the close molecular proximity with FCGR2A, FCGR2B and FCGR3B , additional polymorphisms within these genes and FCGR haplotypes were examined to refine the extent of association with RA. Biallelic polymorphisms in FCGR2A , FCGR2B and FCGR3B were examined for association with RA in two well characterized UK Caucasian and North Indian/Pakistani cohorts, in which FCGR3A genotyping had previously been undertaken. Haplotype frequencies and linkage disequilibrium were estimated across the FCGR locus and a model-free analysis was performed to determine association with RA. This was followed by regression analysis, allowing for phase uncertainty, to identify the particular haplotype(s) that influences disease risk. Our results reveal that FCGR2A, FCGR2B and FCGR3B were not associated with RA. The haplotype with the strongest association with RA susceptibility was the FCGR3A–FCGR3B 158V-NA2 haplotype (odds ratio 3.18, 95% confidence interval 1.13–8.92 [ P = 0.03] for homozygotes compared with all genotypes). The association was stronger in the presence of nodules (odds ratio 5.03, 95% confidence interval 1.44–17.56; P = 0.01). This haplotype was also more common in North Indian/Pakistani RA patients than in control individuals, but not significantly so. Logistic regression analyses suggested that FCGR3A remained the most significant gene at this locus. The increased association with an FCGR3A–FCGR3B haplotype suggests that other polymorphic variants within FCGR3A or FCGR3B , or in linkage disequilibrium with this haplotype, may additionally contribute to disease pathogenesis.
