Dataset Information

Association of variation in Fcgamma receptor 3B gene copy number with rheumatoid arthritis in Caucasian samples.

ABSTRACT: OBJECTIVE:There is increasing evidence that variation in gene copy number (CN) influences clinical phenotype. The low-affinity Fcgamma receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment to sites of inflammation and activation of polymorphonuclear neutrophils (PMNs). Given recent evidence that low FCGR3B CN is a risk factor for systemic but not organ-specific autoimmune disease and the potential importance of PMN in the pathophysiology of rheumatoid arthritis (RA), the authors hypothesised that FCGR3B gene dosage influences susceptibility to RA. METHODS:FCGR3B CN was measured in 643 cases of RA and 461 controls from New Zealand (NZ), with follow-up analysis in 768 cases and 702 controls from the Netherlands and 250 cases and 211 controls from the UK. All subjects were of Caucasian ancestry. RESULTS:Significant evidence for an association between CN <2 and RA was observed in the Dutch cohort (OR 2.01 (95% CI 1.37 to 2.94), p=3 x 10-4) but not in the two smaller cohorts (OR 1.45 (95% CI 0.92 to 2.26), p=0.11 and OR 1.33 (95% CI 0.58 to 3.02), p=0.50 for the NZ and UK populations, respectively). The association was evident in a meta-analysis which included a previously published Caucasian sample set (OR 1.67 (95% CI 1.28 to 2.17), p=1.2 x 10-4). CONCLUSIONS:One possible mechanism to explain the association between reduced FCGR3B CN and RA is the reduced clearance of immune complex during inflammation. However, it is not known whether the association between RA and FCGR3B CN is aetiological or acts as a proxy marker for another biologically relevant variant. More detailed examination of genetic variation within the FCGR gene cluster is required.

SUBMITTER: McKinney C

PROVIDER: S-EPMC3670580 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Association of variation in Fcgamma receptor 3B gene copy number with rheumatoid arthritis in Caucasian samples.

McKinney Cushla C Fanciulli Manuela M Merriman Marilyn E ME Phipps-Green Amanda A Alizadeh Behrooz Z BZ Koeleman Bobby P C BP Dalbeth Nicola N Gow Peter J PJ Harrison Andrew A AA Highton John J Jones Peter B PB Stamp Lisa K LK Steer Sophia S Barrera Pilar P Coenen Marieke J H MJ Franke Barbara B van Riel Piet L C M PL Vyse Tim J TJ Aitman Tim J TJ Radstake Timothy R D J TR Merriman Tony R TR

Annals of the rheumatic diseases 20100514 9

<h4>Objective</h4>There is increasing evidence that variation in gene copy number (CN) influences clinical phenotype. The low-affinity Fcgamma receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment to sites of inflammation and activation of polymorphonuclear neutrophils (PMNs). Given recent evidence that low FCGR3B CN is a risk factor for systemic but not organ-specific autoimmune disease and the potential importance of PMN in the pathophysiolo ...[more]

PMID: 20472591

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Project description:BACKGROUND: Fc gamma receptors (Fc?Rs) play a crucial role in immunity by linking IgG antibody-mediated responses with cellular effector and regulatory functions. Genetic variants in these receptors have been previously identified as risk factors for several chronic inflammatory conditions. The present study aimed to investigate the presence of copy number variations (CNVs) in the FCGR3B gene and its potential association with the autoimmune disease rheumatoid arthritis (RA). METHODOLOGY/PRINCIPAL FINDINGS: CNV of the FCGR3B gene was studied using Multiplex Ligation Dependent Probe Amplification (MLPA) in 518 Dutch RA patients and 304 healthy controls. Surprisingly, three independent MLPA probes targeting the FCGR3B promoter measured different CNV frequencies, with probe#1 and #2 measuring 0 to 5 gene copies and probe#3 showing little evidence of CNV. Quantitative-PCR correlated with the copy number results from MLPA probe#2, which detected low copy number (1 copy) in 6.7% and high copy number (?3 copies) in 9.4% of the control population. No significant difference was observed between RA patients and the healthy controls, neither in the low copy nor the high copy number groups (p-values?=?0.36 and 0.71, respectively). Sequencing of the FCGR3B promoter region revealed an insertion/deletion (indel) that explained the disparate CNV results of MLPA probe#1. Finally, a non-significant trend was found between the novel -256A>TG indel and RA (40.7% in healthy controls versus 35.9% in RA patients; P?=?0.08). CONCLUSIONS/SIGNIFICANCE: The current study highlights the complexity and poor characterization of the FCGR3B gene sequence, indicating that the design and interpretation of genotyping assays based on specific probe sequences must be performed with caution. Nonetheless, we confirmed the presence of CNV and identified novel polymorphisms in the FCGR3B gene in the Dutch population. Although no association was found between RA and FCGR3B CNV, the possible protective effect of the -256A>TG indel polymorphism must be addressed in larger studies.

Project description:ObjectiveTo determine whether copy number variations (CNVs) in FCGR3A and FCGR3B are associated with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Taiwanese individuals.MethodsFCGR3A and FCGR3B CNV genotypes were determined in 846 patients with SLE, 948 patients with RA, and 1,420 healthy control subjects, using custom TaqMan CNV assays. The FCGR3A and FCGR3B CNV genotypes were compared between healthy control subjects and patients and among patients stratified according to clinical characteristics.ResultsA low (<2) FCGR3A copy number was significantly associated with SLE (for <2 copies versus 2 copies, P = 5.06 × 10(-4) , false discovery rate-corrected P [PFDR ] = 0.001, odds ratio [OR] 3.26, 95% confidence interval [95% CI] 1.68-6.35) and RA (for <2 copies versus 2 copies, P = 5.83 × 10(-4) , PFDR = 0.0012, OR 2.82, 95% CI 1.56-5.1). A low FCGR3B copy number was also significantly associated with SLE (for <2 copies versus 2 copies, P = 0.0032, PFDR = 0.0032, OR 1.59, 95% CI 1.17-2.18). Notably, a high (>2) FCGR3A copy number was also associated with SLE (for >2 copies versus 2 copies, P = 0.003, PFDR = 0.0061, OR 1.6, 95% CI 1.17-2.18). Additionally, the FCGR3A low copy number genotype was significantly enriched in subsets of patients with SLE (those with ulcer, arthritis, rash, discoid rash, photosensitivity, nephritis, leukopenia, thrombocytopenia, depressed complement levels, and autoantibody positivity) and patients with RA (those positive for rheumatoid factor) compared with healthy control subjects. The FCGR3B low copy number genotype was also significantly enriched in SLE patients with ulcer, rash, discoid rash, photosensitivity, ascites, nephritis, complement level depression, and anti-double-stranded DNA antibody positivity compared with control subjects. However, FCGR3B CNVs were not associated with RA susceptibility (for <2 copy numbers versus 2 copy numbers, P = 0.3584, OR 1.15, 95% CI 0.85-1.55) and clinical characteristics.ConclusionIn Taiwanese individuals, a low FCGR3A copy number is a common risk factor for SLE and RA, while a low FCGR3B copy number confers a risk of SLE but not RA.

Dataset Information

Association of variation in Fcgamma receptor 3B gene copy number with rheumatoid arthritis in Caucasian samples.

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Association of variation in Fcgamma receptor 3B gene copy number with rheumatoid arthritis in Caucasian samples.

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