Genetic risk factors for infection in patients with early rheumatoid arthritis

We analyzed clinical and genetic factors contributing to infections in 457 subjects with early rheumatoid arthritis (RA) enrolled in a prospective, 1-year clinical trial of methotrexate and the TNF inhibitor etanercept. Subjects were genotyped for the following single nucleotide polymorphisms (SNPs): (TNF -308, -238, and + 488); lymphotoxin-alpha (LTA) (LTA + 249, + 365, and + 720); and Fc gamma receptors FCGR2A 131 H/R; FCGR3A 176 F/V; and FCGR3B NA 1/2 and genotypes were correlated with infections. At least one URI was noted in 52% of subjects (99/191) with the NA2/NA2 genotype of the neutrophil-specific FCGR3B gene, compared to 42% (77/181) of those with the NA1/NA2 genotype and 39% (23/59) of those with the NA1/NA1 genotype (P = 0.038). Urinary tract infection (UTI) was associated with the TNF -238 A (odds ratio(OR) 2.56, 95% confidence interval (CI) 1.05-6.25) and LTA +365 C (OR 1.73, 95% CI 1.07-2.79) alleles, and marginally with the FCGR3A F allele (OR 1.72, 95% CI 0.99-3.00). There was a striking linear correlation between UTI and the number of risk alleles defined by these three SNPs (P < 0.001), suggesting an additive effect on susceptibility. These findings have important implications for the role of genetics in susceptibility to bacterial and viral infections.     

Fc-gamma receptor 3A polymorphism predicts the incidence of urinary tract infection in kidney-transplant recipients

We investigated the impact of polymorphisms in host innate immunoregulatory genes on the development of infectious complications after kidney transplantation (KT). The single-nucleotide polymorphisms (SNPs) of C1QA [276 A/G], FCGR2A [131 H/R], and FCGR3A [158 F/V], genes encoding the Fc gamma receptor (FcγR), were analyzed in 81 KT recipients in relation to the occurrences of postoperative infectious complications within 30 days after KT. Consistent with a lower affinity of the isoform encoded by the FCGR3A [158 F] to both IgG1 and IgG3, a significantly higher incidence of urinary tract infections (UTIs) was observed in the FCGR3A [158 F/V or F/F] individuals (65.5%) than in the FCGR3A [158 V/V] individuals (34.5%) following KT. The combination of FCGR2A and FCGR3A SNPs further stratified the incidence of UTIs, regardless of C1QA SNP following KT. No differences were observed in the incidence of fungal or cytomegalovirus infections with respect to the 3 gene polymorphisms.In conclusion, our findings indicate that FcγR SNPs are predisposing factors for UTIs after KT. This study provides a foundation for further prospective studies on a larger scale.     

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

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.     

Associations between FCGR polymorphisms and immune thrombocytopenia: A meta‐analysis

Several studies already explored associations between Fc gamma receptor (FCGR) polymorphisms and immune thrombocytopenia (ITP), but the results of these studies were not consistent. Consequently, we conducted a meta‐analysis of relevant studies to better analyse the effects of FCGR polymorphisms on individual susceptibility to ITP. PubMed, Web of Science, Embase and CNKI were searched for eligible studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Totally 17 studies were eligible for analyses (1200 cases and 1723 controls). Significant associations with ITP were observed for FCGR3A F158V polymorphism in dominant (P < 0.0001, OR = 0.47, 95% CI 0.39‐0.57), recessive (P < 0.0001, OR = 2.03, 95% CI 1.58‐2.61), overdominant (P < 0.0001, OR = 1.42, 95% CI 1.19‐1.69) and allele (P < 0.0001, OR = 0.58, 95% CI 0.51‐0.65) models in overall analyses. But we did not observe any significant associations with ITP for FCGR2A H131R and FCGR2B I232T polymorphisms in overall analyses. Subgroup analyses by ethnicity yielded similar positive results for FCGR3A F158V polymorphism in both Asians and Caucasians. Furthermore, subgroup analyses by type of disease revealed that FCGR2A H131R polymorphism was significantly associated with childhood‐onset ITP, and FCGR3A F158V polymorphism was significantly associated with both childhood‐onset and adult‐onset ITP. In summary, our findings suggested that FCGR2A H131R polymorphism may serve as a potential genetic biomarker of childhood‐onset ITP, while FCGR3A F158V polymorphism may serve as a potential genetic biomarker of both childhood‐onset and adult‐onset ITP.     

Association of Fcgamma receptor IIb polymorphism with susceptibility to systemic lupus erythematosus in Chinese: a common susceptibility gene in the Asian populations

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.     

Association of rheumatoid factor production with FcgammaRIIIa polymorphism in Taiwanese rheumatoid arthritis

Fcgamma receptors (FcgammaR) impact upon the development of inflammatory arthritis through immune complex stimulation and proinflammatory cytokine production. FcgammaRIIa, FcgammaRIotaIotaIotaa and FcRgammaIIIb polymorphisms were genotyped in 212 rheumatoid arthritis (RA) patients and 371 healthy control subjects using an allelic-specific polymerase chain reaction (PCR). No significant skewing in the distribution of FcgammaRIIa H/R131, FcgammaRIIIa F/V158 and FcgammaRIIIb NA1/NA2 was found between RA patients and healthy control subjects. However, a significant skewing distribution of the FcgammaRIIIa F/V158 polymorphism was observed between rheumatoid factor (RF)-positive versus RF-negative RA patients (P = 0.01). The low-affinity FcgammaRIIIa F158 allele seems to have a protective role in RF production, in comparison with the FcgammaRIIIa V158 allele (P = 0.004; OR = 0.485; 95% CI: 0.293-0.803). A high frequency of FcgammaRIIIa F/F158 was identified in RA patients with negative RF compared with RF-positive patients (for FF158 versus FV158 + VV158; P = 0.002; OR = 0.372; 95% CI: 0.194-0.713). In addition, no association was found between FcgammaRIIa H/R131, FcgammaRhoIIIa F/V158 and FcgammaRIIIb NA1/NA2 polymorphisms and other clinical parameters. The results of this study suggest that three activating FcgammaRs polymorphisms lack association with RA but FcgammaIIIa F/V158 polymorphism may influence RF production and IgG RF immune complex handling in Taiwanese RA patients.     

Evidence that deletion at FCGR3B is a risk factor for systemic sclerosis

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.     

Evidence for both copy number and allelic (NA1/NA2) risk at the FCGR3B locus in systemic lupus erythematosus

The Fcγ-receptor locus on chromosome 1q23 shows copy-number variation (CNV), and it has previously been shown that individuals with reduced numbers of copies of the Fcγ-receptor-IIIB gene (FCGR3B) have an increased risk of developing systemic lupus erythematosus (SLE). It is not understood whether the association arises from FCGR3B (CD16b) itself, is observed because of linkage disequilibrium with actual causal alleles and/or is an effect of CNV on flanking FCGR genes. Thus, we extended this previous work by genotyping the FCGR3B alleles NA1/NA2 and re-assaying CNV using a paralogue ratio test assay in a family study (365 families). We have developed a novel case/pseudo-control approach to analyse family data, as the phase of copy number (CN) is not known in parents and cannot always be inferred in offspring. The results, obtained by fitting logistic regression models, confirm the association of low CN of FCGR3B with SLE (P=0.04). The risk conferred by low copies (<2) was contingent on FCGR3B allotype, being greater for deletion of NA1 than the for lower-affinity NA2. The simpler model with just CN was rejected in favour of the biallelic-CN model (P=0.03). We observed a correlation (R²=0.75, P<0.0001) between FCGR3B CNV and neutrophil expression in both healthy controls and patients with SLE. Our results suggest that one mechanism by which CNV at this locus confers disease risk is directly as a result of reduced FcγRIIIb function, either because of reduced expression (related to CNV) or because of reduced affinity for its ligand (NA1/NA2 allotype).     

Simple genotyping of functional polymorphisms of the human immunoglobulin G receptors CD16A and CD32A: a reference cell panel

The Fcγ receptors CD16A and CD32A connect the innate and the adaptive immune responses by transmitting activating signals to natural killer lymphocytes and myeloid cells upon recognition of antigen–immunoglobulin G (IgG) complexes. Two allelic dimorphisms of these receptors, valine/phenylalanine-158 of CD16A and histidine/arginine-131 of CD32A, modulate their affinity for certain human IgG subclasses. Furthermore, these polymorphisms are clinically relevant because they modify the susceptibility, the clinical course and the response to therapy of several human diseases. Genotyping of CD16A and CD32A alleles, encoded by FCGR3A and FCGR2A , respectively, is complicated by the fact that they both belong to families of highly homologous genes. In this study, we present an original method for genotyping the FCGR3A and FCGR2A dimorphisms based on the technique of polymerase chain reaction with confronting two-pair primers. The new method simplifies the analysis of FCGR3A and FCGR2A because the two alleles of each gene are detected simultaneously in a single reaction and separated, with no further manipulations, by their different electrophoretic mobilities in regular agarose gels. We also present the CD16A and CD32A genotypes of cells from the Tenth International Histocompatibility Workshop, which can serve as a reference cell panel for investigating the influence of CD16A and CD32A polymorphisms on human health.     

Nucleotide sequence of a new Fc gamma receptor IIIB allele that codes for a neutrophil antigen

A new allele of the human neutrophil antigen (HNA) system (tentatively called NA2M) was discovered and its nucleotide sequence was determined. NA2M differs in a single nucleotide (193G-->A) from FCGR3B*2(NA2), resulting in an amino acid change (54Glu-->Lys). The frequency of the NA2M gene in the Japanese population was estimated to be 0.008. Granulocytes of individuals possessing NA2M reacted with HNA-1b(NA2)-specific monoclonal antibody (TAG2) in the GIFT assay.     

Fc gamma RIIa, IIIa and IIIb polymorphisms in Turkish children susceptible to recurrent infectious diseases

Abstract The efficacy of IgG-induced Fc gamma receptor (FcγR) function displays interindividual heterogeneity due to genetic polymorphisms of three FcγR subclasses: FcγRIIa, FcγRIIIa and FcγRIIIb. FcγR polymorphisms may contribute to disease susceptibility or may alter disease course. The aim of this study is to examine FcγR gene polymorphisms in Turkish children with recurrent respiratory tract infections and without well known humoral immunodeficiencies. For the patients in the study group (n=52), recurrent infection was defined as the presence of at least six infection episodes a year. Seventy-one healthy children with a maximum of two infections in a year were enrolled as the control group. Subjects in both groups had no abnormalities in serum immunoglobulins, IgG subsets and specific antibody levels. For FcγRIIa: H131H, H131R, R131R genotypes and 131R, 131H alleles; for FcγRIIIa: F158F, F158V, V158V genotypes and 158F, 158V alleles; and for FcγRIIIb: –NA1/NA1, NA1/NA2, NA2/NA2 genotypes and NA1, NA2 alleles were determined by using amplification refractory mutation system polymerase chain reaction (ARMS-PCR). Compared with the control group, the FcγRIIa-R131R genotype and 131R allele were found to be significantly elevated in the study group, and FcγRIIa-H131H genotype and 131H allele in the study group were significantly lower than in the control group. Genotypes and alleles related with FcγRIIIa and FcγRIIIb gene polymorphisms did not show any significant difference between the study and control groups. FcγRIIa gene polymorphism (R131R) may increase the risk and susceptibility for recurrent infectious diseases in children.     

Confirmation of association of FCGR3B but not FCGR3A copy number with susceptibility to autoantibody positive rheumatoid arthritis

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.     

Flow cytometric assay for determination of FcgammaRIIIA-158 V/F polymorphism

A single nucleotide polymorphism (SNP) of the FCGR3A gene results in two allotypes of Fcgamma receptor IIIA (FcgammaRIIIA) with valine (V) or phenylalanine (F) at amino acid 158. Since the FcgammaRIIIA-158 V/F polymorphism is associated with the efficacy of monoclonal antibody (mAb) treatment and a risk factor for autoimmune disease, widely applicable methods to assess the SNP are needed. We developed a novel flow cytometric test for this polymorphism using a mAb that recognized only the FcgammaRIIIA-158 V allele (MEM-154) together with a mAb that detected both FcgammaRIIIA-158 alleles (3G8). The expression of both FcgammaRIIIA epitopes on natural killer (NK) cells from 37 healthy donors were measured and compared to the FCGR3A genotype determined by a 5' nuclease assay. FcgammaRIIIA expression levels in individuals with identical FCGR3A genotypes varied considerably, resulting in overlapping immunofluorescences by both 3G8 and MEM-154 between FcgammaRIIIA-158 V/F allotypes. However, the ratio between fluorescences measured using those mAbs in a single individual predicted the FCGR3A genotype with 100% sensitivity and specificity. The novel flow cytometric assay for the FcgammaRIIIA-158 V/F polymorphism that is based on the MEM-154/3G8 fluorescence ratio requires commercially available reagents and a three-color flow cytometer only.     

Rapid single-step FCGR3A genotyping based on SYBR Green I fluorescence in real-time multiplex allele-specific PCR

A polymorphism at position 559 in the cDNA of the FCGR3A gene encoding the FcgammaRIIIa generates two allotypes with either a valine (Val) or a phenylalanine (Phe) at amino acid position 158. This polymorphism is of major importance in immunopathology and in pharmacogenetics, especially monoclonal antibody treatments. In this study, we report a single-step and single-tube method for FCGR3A-158V/F genotyping by real-time multiplex allele-specific PCR and melting curve analysis in the presence of SYBR Green I fluorescent dye. Results obtained from 113 samples showed 100% accuracy compared to those obtained with a conventional PCR-based allele-specific restriction assay. Although this method requires expensive equipment, it is inexpensive in terms of consumables. It is also very rapid, reliable and suitable for large-scale analysis.     

FcγRIIa and FcγRIIIb polymorphisms and associations with clinical manifestations in systemic lupus erythematosus patients

Abstract

In this study, we aimed to investigate whether the distribution of the FcγRIIa and FcγRIIIb polymorphisms determines susceptibility to systemic lupus erythematosus (SLE) and acts as predictors of SLE clinical manifestations in the Brazilian patients. A total of 157 patients that fulfilled the American College of Rheumatology classification criteria for SLE and 160 healthy volunteers were included in this study. FCGR2A and FCGR3B genotypes were determined by polymerase chain reaction-based allotyping methods with allele-specific primers; the clinical features were obtained from the patients' official medical records. In the case of FcγRIIa polymorphism, it was observed association of the allele FCGR2A-R-131 (p?=?0.02, odds ratio (OR)=1.44) and genotype RR-131 (p?=?0.03, OR?=?2.09) with SLE. These associations were higher with allele (p?<?0.01, OR?=?1.67) as well genotype (p?=?0.01, OR?=?2.85) when lupus nephritis was considered. In contrast, the allele FCGR2A-H-131 was associated with susceptibility to arthritis and anti-DNA antibodies (p?=?0.05 for both). As for FcγRIIIb polymorphism, skewing did not differ significantly between patients and controls, however the genotype FCGR3B*02*02 was associated with susceptibility to arthritis (p?=?0.02) and malar rash (p?=?0.03), but no association with nephritis was found. The results demonstrate that FcγRIIa polymorphism is associated with susceptibility to SLE in Brazilian patients, whereas for FcγRIIIb polymorphism no association was found. However, notably, both polymorphisms present allelic variants that influence the clinical manifestations and may contribute to the pathogenesis of the disease. In addition, to our knowledge, this is the first study considering the frequency of FcγRIIIb polymorphism in Brazilian SLE patients.     

Genetic variations in low-to-medium-affinity Fcγ receptors and autoimmune neutropenia in early childhood in a Danish cohort

Autoimmune neutropenia (AIN) in early childhood is caused by autoantibodies directed against antigens on the neutrophil membrane and is a frequent cause of neutropenia in children. Association of AIN with Fcγ receptor (FCGR) 3B variants is well described. In this study, we investigate genetic variations in the FCGR locus and copy number variation of FCGR3B. A total of 130 antibody-positive AIN patients, 64 with specific anti-HNA-1a antibodies and 66 with broad-reacting anti-FcγRIIIb antibodies, were genotyped with a multiplex ligation probe assay and compared with healthy controls. Positive findings were confirmed with real-time q-PCR. We determined copy numbers of the FCGR2 and FCGR3 genes and the following SNPs: FCGR2A Q62W (rs201218628), FCGR2A H166R (rs1801274), FCGR2B I232T (rs1050501), FCGR3A V176F (rs396991), haplotypes for FCGR2B/C promoters (rs3219018/rs780467580), FCGR2C STOP/ORF and HNA-1 genotypes in FCGR3B (rs447536, rs448740, rs52820103, rs428888 and rs2290834). Generally, associations were antibody specific, with all associations being representative of the anti-HNA-1a-positive group, while the only association found in the anti-FcγRIIIb group was with the HNA-1 genotype. An increased risk of AIN was observed for patients with one copy of FCGR3B; the HNA genotypes HNA-1a, HNA-1aa or HNA-1aac; the FCGR2A 166H and FCGR2B 232I variations; and no copies of FCGR2B 2B.4. A decreased risk was observed for HNA genotype HNA-1bb; FCGR2A 166R; FCGR2B 232T; and one copy of FCGR2B promoter 2B.4. We conclude that in our Danish cohort, there was a strong association between variation in the FCGR locus and AIN. The findings of different genetic associations between autoantibody groups could indicate the presence of two different disease entities and disease heterogeneity.     

Role of neutrophil Fc gamma RIIa (CD32) and Fc gamma RIIIb (CD16) polymorphic forms in phagocytosis of human IgG1- and IgG3-opsonized bacteria and erythrocytes.

The four subclasses of IgG have different biological activities associated with their Fc regions. Fc gamma receptors on leucocytes (Fc gamma R) mediate binding and phagocytosis of opsonized particles. Two structurally and functionally distinct allelic polymorphisms of the Fc gamma R have been defined: the H/R131 forms of Fc gamma RIIa (CD32), and the neutrophil antigen 1 (NA1)/NA2 forms of Fc gamma RIIIb (CD16). In this study the activities of allotypes of CD16 are analysed with antibacterial IgG subclass antibodies and with IgG1 and IgG3 anti-Rhesus D, and the activities of CD32 with IgG1 and IgG3 anti-Rhesus D. With respect to the allotypes of CD16, polymorphonuclear leucocytes (PMN) homozygous for Fc gamma RIIb-NA2 exhibited a lower (21-25%) IgG1-mediated phagocytosis of Staphylococcus aureus strain Wood (STAW), Haemophilus influenzae type b (Hib), and Neisseria meningitidis group B (NMen) than IIIb-NA1 PMN. The difference was apparent only when the micro-organisms were opsonized in the absence of complement, and was furthermore enhanced (34-52%) upon blockade of Fc gamma RIIa. In addition, monoclonal IgG3 anti-D-mediated rosette formation and phagocytosis was consistently found to be lower (16%) with Fc gamma RIIIb-NA2 than with IIIb-NA1 PMN. For the allotypes of CD32 we now show that IgG3 anti-D sensitized erythrocytes formed more (50%) rosettes and were phagocytosed at a higher rate with PMN carrying Fc gamma RIIa-H131 than with PMN carrying IIa-R131. Heterozygous Fc gamma RIIa-H/R131 PMN exhibited intermediate phagocytic activity in this respect. This study illustrates a critical role of Fc gamma R allotypes in functional interactions with biologically relevant IgG subclass antibodies.     

Polymorphism of FCGR3A gene in sarcoidosis

We showed increased level of immune complexes (ICs) with mycobacterial heat shock proteins (Mtb-hsp) and increased expression of receptors for Fc fragment of immunoglobulin G (FcγR) I–III on blood monocytes with their increased phagocytic activity, responsible for clearance of these ICs in sarcoidosis (SA). Since FcγRIIIa is the most crucial in this process, we genotyped 77 SA patients and 143 healthy controls with polymerase chain reaction for V158F polymorphism of FCGR3A gene, encoding FcγRIIIa. We revealed significantly higher percentage of 158F and 158FF and lower of 158FV variants in Stage I of SA versus controls. Conversely, in Stage II of SA, we found increase in 158VV homozygotes versus controls. We also showed significant increase of 158F and 158FF variants in Stage I vs II and of 158V in Stage II vs I. Therefore, in Stage I, 158F allele may cause decreased FcγRIIIa affinity and clearance of ICs, whereas in Stage II, 158V allele may cause effective FcγRIIIa affinity to ICs with e.g. mycobacteria, their phagocytosis, Mtb-hsp secretion with ICs formation, Mtb-hsp epitope spread and subsequent immune reaction. Thus, V158F polymorphism of FCGR3A may explain the immunocomplexemia in our patients and might serve as prognostic marker of clinical course of sarcoidosis.     

Understanding the Genomic Structure of Copy‐Number Variation of the Low‐Affinity Fcγ Receptor Region Allows Confirmation of the Association of FCGR3B Deletion with Rheumatoid Arthritis

Fcγ receptors are a family of cell–surface receptors that are expressed by a host of different innate and adaptive immune cells, and mediate inflammatory responses by binding the Fc portion of immunoglobulin G. In humans, five low‐affinity receptors are encoded by the genes FCGR2A , FCGR2B , FCGR2C , FCGR3A , and FCGR3B , which are located in an 82.5‐kb segmental tandem duplication on chromosome 1q23.3, which shows extensive copy‐number variation (CNV). Deletions of FCGR3B have been suggested to increase the risk of inflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis (RA). In this study, we identify the deletion breakpoints of FCGR3B deletion alleles in the UK population and endogamous native American population, and show that some but not all alleles are likely to be identical‐by‐descent. We also localize a duplication breakpoint, confirming that the mechanism of CNV generation is nonallelic homologous recombination, and identify several alleles with gene conversion events using fosmid sequencing data. We use information on the structure of the deletion alleles to distinguish FCGR3B deletions from FCGR3A deletions in whole‐genome array comparative genomic hybridization (aCGH) data. Reanalysis of published aCGH data using this approach supports association of FCGR3B deletion with increased risk of RA in a large cohort of 1,982 cases and 3,271 controls (odds ratio 1.61, P = 2.9×10^?3).