Fcγ receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: Contribution of FCGR2B to genetic susceptibility

Objective

Human low‐affinity Fcγ receptors (FcγR) constitute a clustered gene family located on chromosome 1q23, that consists of FcγRIIA, IIB, IIC, IIIA, and IIIB genes. FcγRIIB is unique in its ability to transmit inhibitory signals, and recent animal studies demonstrated a role for FcγRIIB deficiency in the development of autoimmunity. Genetic variants of FcγRIIA, IIIA, and IIIB and their association with systemic lupus erythematosus (SLE) have been extensively studied in various populations, but the results were inconsistent. To examine the possibility that another susceptibility gene of primary significance exists within the FcγR region, we screened for polymorphisms of the human FCGR2B gene, and examined whether these polymorphisms are associated with SLE.

Methods

Variation screening of FCGR2B was performed by direct sequencing and polymerase chain reaction (PCR)‐single‐strand conformation polymorphism methods using complementary DNA samples. Genotyping of the detected polymorphism was done using genomic DNA, with a specific genotyping system based on nested PCR and hybridization probing. Association with SLE was analyzed in 193 Japanese patients with SLE and 303 healthy individuals. In addition, the same groups of patients and controls were genotyped for the previously known polymorphisms of FCGR2A, FCGR3A, and FCGR3B.

Results

We detected a single‐nucleotide polymorphism in FCGR2B, (c.695T>C), coding for a nonsynonymous substitution, Ile232Thr (I232T), within the transmembrane domain. The frequency of the 232T/T genotype was significantly increased in SLE patients compared with healthy individuals. When the same patients and controls were also genotyped for FCGR2A‐131R/H, FCGR3A‐176V/F, and FCGR3B‐NA1/2 polymorphisms, FCGR3A‐176F/F showed significant association. Two‐locus analyses suggested that both FCGR2B and FCGR3A may contribute to SLE susceptibility, while the previously reported association of FCGR3B was considered to be secondary and derived from strong linkage disequilibrium with FCGR2B.

Conclusion

These results demonstrate the association of a new polymorphism of FCGR2B (I232T) with susceptibility to SLE in the Japanese.

     

Genetic susceptibility and haplotype analysis between Fcgamma receptor IIB and IIIA gene with systemic lupus erythematosus in Chinese population

The objective of this study is to understand the role of FcgammaRIIB and FcgammaRIIIA gene in susceptibility to systemic lupus erythematosus (SLE), and to examine possible susceptible haplotypes between two genes. A total of 119 patients with SLE from 95 nuclear families, aged from 14 to 78 years, were selected according to 1997 criteria of American College of Rheumatology. In addition, 316 family members of these patients were also genotyped. A family-based association study was used to explore the relationship between gene polymorphism and SLE. We studied 13 single-nucleotide polymorphisms (SNPs) encoding non-synonymous substitution in the FcgammaRIIB and FcgammaRIIIA gene (four SNPs in the FcgammaRIIB gene and nine SNPs in the FcgammaRIIIA gene) with respect to genetic susceptibility to SLE. All SNPs were genotyped by restriction fragment length polymorphism method. Among 13 SNPs, univariate (single-marker) family-based association tests showed that variant alleles at only four SNPs (rs10917661 and rs1050501, in exon 2 and exon 5 of FcgammaRIIB gene, rs403016 and rs428888, in exon3 of FcgammaRIIIA gene respectively) were significantly associated with genetic susceptibility to SLE. Furthermore, the haplotype-specific FBATs showed 50Ter-225Thr (34.1%, in FcgammaRIIB gene) and 72Arg-118Asn (40%, in the FcgammaRIIIA gene) haplotype were more frequently transmitted in SLE than other haplotypes (Z = 3.539, P = 0.00042; Z = 2.678, P = 0.007412 respectively). But haplotypes were not found between FcgammaRIIB and FcgammaRIIIA gene Our results suggest that there were meaningful haplotype in FcgammaRIIIA and FcgammaRIIB gene respectively. FcgammaRIIIA and FcgammaRIIB genes in the pathogenesis of SLE may play an independent role in Chinese population.     

Genetic linkage and association of Fcgamma receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus

OBJECTIVE: Although low-affinity alleles of human Fcgamma receptor types IIA and IIIA (FcgammaRIIA and FcgammaRIIIA, respectively) polymorphisms have been associated with systemic lupus erythematosus (SLE) in case-control studies, the relative contribution of these genes to SLE susceptibility has not been resolved. METHODS: We analyzed the distribution of alleles of FcgammaRIIA, FcgammaRIIIA, and FcgammaRIIIB in 126 multiplex-SLE pedigrees and FcgammaRIIA and FcgammaRIIIA in a case-control replication study, using allele-specific polymerase chain reaction and direct sequencing of genomic DNA. Statistical tests of association were performed to detect evidence of linkage between the single nucleotide polymorphisms and SLE. RESULTS: We found evidence for linkage at both the FcgammaRIIIA (single-point nonparametric linkage [NPL] 1.8, P = 0.038; multipoint NPL 2.7, P = 0.004) and the FcgammaRIIA (single-point NPL 2.0, P = 0.021; multipoint NPL 2.6, P = 0.006) loci, but not the FcgammaRIIIB locus. Family-based tests of association demonstrated increased transmission of the low-affinity F176 allele at the FcgammaRIIIA locus (odds ratio [OR] 2.18, P = 0.0005 by transmission disequilibrium test and P = 0.002, by pedigree disequilibrium test [PDT]), but little evidence of preferential transmission of alleles at FcgammaRIIA (P = 0.089 by PDT). Stratification by ethnicity showed preferential transmission of the associated FcgammaRIIIA allele both in families of African American ancestry and in those of European American ancestry. Despite significant linkage disequilibrium between these genes, 2- and 3-locus haplotype analysis of the extended Fcgamma receptor cluster did not reveal any significant association beyond that observed with FcgammaRIIIA alone. In a large case-control replication study of 438 patients with SLE and 219 controls, FcgammaRIIIA provided the strongest evidence of an FcgammaR-SLE association (additive model: V/V 176 versus V/F 176 OR 1.51, V/V 176 versus F/F 176 OR 1.98, P = 0.007). CONCLUSION: To our knowledge, these data are the first to demonstrate linkage and both family-based and case-control-based association of FcgammaRIIIA with SLE. These data provide genetic evidence supporting a role for the physiologically relevant single nucleotide polymorphism of the FcgammaRIIIA gene in the pathophysiology of this complex genetic disease.     

FCGR3A and FCGR2A polymorphisms may not correlate with response to alemtuzumab in chronic lymphocytic leukemia

The in vivo mechanism of action of alemtuzumab (anti-CD52; Campath-1H) remains unclear. With rituximab, FCGR3A and FCGR2A high-affinity polymorphisms have been associated with clinical response in lymphoma but not in CLL, suggesting potential divergent mechanisms of action between these 2 diseases. Herein, we examined FCGR3A (V/V, n = 4; V/F, n = 10; F/F, n = 19) and FCGR2A (A/A, n = 5; H/A, n = 22; H/H, n = 6) polymorphisms in 36 patients with relapsed CLL who were treated with thrice-weekly alemtuzumab for 12 weeks to assess the potential influence these high-affinity FcgammaR receptor polymorphisms had on response to alemtuzumab. Response to alemtuzumab was similar regardless of FCGR3A polymorphism (V/V, 25%; V/F, 40%; F/F, 32%) or FCGR2A polymorphism (A/A, 40%; H/A, 32%; H/H, 33%). These findings indicate that FCGR3A and FCGR2A polymorphisms may not predict response to alemtuzumab in CLL. Future studies examining larger cohorts of alemtuzumab-treated patients with CLL will be required to definitively determine the predictive value of specific FCGR polymorphisms to treatment response.     

FCGR2A基因多态性与系统性红斑狼疮相关性研究

目的 明确FCGR2A基因H131／R131多态性在中国人群中的分布，探讨该位点是否与系统性红斑狼疮(SLE)的发病有关。方法 应用Taqman MGB方法对340例SLE病人，300例患者父母和183名正常人的H131／R131多态性位点进行大规模等位基因分型，病例对照研究应用χ^2检验，家系为基础的传递不平衡检验应用ETDT22软件。结果 病例对照研究提示SLE组和正常组之间的等位基因频率无明显差异(P=0．413)，传递不平衡检验证实该位点在中国人群SLE家系中无优势传递(P=0．6049)。结论 在中国汉族人群中FCGR2A H131／R131多态性位点与SLE的发病不存在相关性。     

Fcgamma receptor polymorphisms in systemic lupus erythematosus: association with disease and in vivo clearance of immune complexes

OBJECTIVE: Fc receptors for IgG (FcgammaR) play a prominent role in the clearance of immune complexes in systemic lupus erythematosus (SLE). Polymorphisms of FcgammaR have been proposed as genetic factors that influence susceptibility to SLE. We analyzed 3 functional FcgammaR polymorphisms in a strictly Caucasian population of SLE patients, and determined the influence of these polymorphisms on the clearance of immune complexes in vivo. METHODS: Genomic DNA was isolated from 230 Caucasian patients with SLE and 154 controls. Amplification of FcgammaR-genomic regions in allotype-specific polymerase chain reactions was used to distinguish the genotypes. In addition, we analyzed the FcgammaR genotypes of 13 patients with SLE who participated in a study determining the half-life of IgG-coated erythrocytes in the blood. RESULTS: We found a strong trend toward skewing of FcgammaRIIa, with an enrichment of the homozygous FcgammaRIIa-R/R131 genotype in patients compared with controls. We did not find a correlation between this genotype and the development of lupus nephritis. However, we established that the half-life of IgG-coated erythrocytes in the blood was prolonged in patients expressing the FcgammaRIIa-R/R131 genotype. The homozygous FcgammaRIIIa-F/F158 genotype was found more frequently in patients with arthritis and/or serositis. CONCLUSION: In Caucasian populations, the R/H polymorphism of FcgammaRIIa is a minor determinant in susceptibility to SLE, whereas the V/F polymorphism of FcgammaRIIIa is associated with a set of disease manifestations. Notably, the R/H polymorphism of FcgammaRIIa affects the clearance of immune complexes in vivo, which may influence the course of a disease such as SLE.     

Genetic background of Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis: association of HLA-DRB1*0901 with microscopic polyangiitis

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.     

The Fcgamma receptor IIIA-158F allele is a major risk factor for the development of lupus nephritis among Caucasians but not non-Caucasians

OBJECTIVE: To determine whether inheritance of Fcgamma receptor (FcgammaR) alleles conferring lower affinity for IgG binding increases the risk of developing lupus nephritis. METHODS: We compared the frequency of low-affinity alleles of two FcgammaR polymorphisms (FcgammaRIIA and FcgammaRIIIA) among 235 patients with systemic lupus erythematosus (SLE) and proven nephritis (nephritis patients) and among 352 SLE patients with no evidence of renal disease (non-nephritis control subjects). The ethnic distribution of patients in the study was 49% Caucasian, 20% Hispanic, 17% Asian/Pacific Islander, 12% African American, and 2% from other ethnic groups. All patients were genotyped for the FcgammaRIIA-131R/H and FcgammaRIIIA-158V/F polymorphisms. We used contingency table analysis to compare allele and genotype distributions for nephritis patients and nonnephritis control subjects, including ethnic-specific strata. Multivariate logistic regression analyses included sex and disease duration as covariates. RESULTS: Univariate and multivariate analyses demonstrated a striking association between the low-affinity FcgammaRIIIA-158F allele and FF genotype and the risk of nephritis among Caucasians, but not among non-Caucasians (multivariate odds ratio [OR] 2.6 for Caucasians with FF genotype), (P = 0.0017). This association was even stronger among Caucasians with severe nephritis (OR 4.4, P < 0.0001). In contrast, inheritance of the low-affinity FcgammaRIIA-131R allele (and RR genotype) was not associated with an increased risk of lupus nephritis among any of the ethnic groups examined. CONCLUSION: The FcgammaRIIIA-158F allele is a major risk factor for the development of lupus nephritis among Caucasians, but not among non-Caucasians. These results suggest that ethnic variation is critical in defining the specific genetic factors underlying the pathogenesis of SLE, and they have important prognostic and therapeutic implications as well.     

Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene.

Given that the FcgammaRIIIa receptor 158V allotype displays a higher affinity for human immunoglobulin G1 and increased antibody-dependent cellular cytotoxicity, the aim of this study was to determine the influence of that FCGR3A polymorphism on the therapeutic response to rituximab, an anti-CD20 humanized immunoglobulin G1 increasingly used in the treatment of non-Hodgkin lymphomas. The FCGR3A-158V/F genotype was determined in 49 patients having received rituximab for a previously untreated follicular non-Hodgkin lymphoma. The clinical response and the disappearance of the BCL2-JH gene rearrangement in both peripheral blood and bone marrow were evaluated at 2 months (M2) and at 1 year (M12). The study population consisted of 20% FCGR3A-158V homozygous patients, 35% FCGR3A-158F homozygous patients, and 45% heterozygous patients (FCGR3A-158F carriers). The objective response rates at M2 and M12 were 100% and 90%, respectively, in FCGR3A-158V homozygous patients compared with 67% (P =.03) and 51% (P =.03), respectively, in FCGR3A-158F carriers. A disappearance of the BCL2-JH gene rearrangement in both peripheral blood and marrow was observed at M12 in 5 of 6 of homozygous FCGR3A-158V patients compared with 5 of 17 of FCGR3A-158F carriers (P =.03). The homozygous FCGR3A-158V genotype was confirmed to be the single parameter associated with clinical and molecular responses by multivariate analysis. This study showed an association between the FCGR3A genotype and clinical and molecular responses to rituximab. This finding will certainly give rise to new pharmacogenetic approaches to the management of patients with non-Hodgkin lymphomas.     

FCGR3A V(176) polymorphism for systemic lupus erythematosus susceptibility in Mexican population

The objective of this study is to establish whether there is an association between the presence of FCGR3A V(176) polymorphism with SLE or its manifestations. We included 94 patients according to the 1982 ACR criteria as well as 98 controls matched by age and gender. The 11 ACR diagnostic criteria were analyzed on the clinical files. The polymorphism FCGR3A V(176) was determined by direct sequencing. There was not an association between the polymorphism FCGR3A V(176) with SLE or its main manifestations. The allelic frequency for F(176) was: 0.80 and 0.72 in cases and controls, respectively (P?=?0.09, IC95%: 0.42?C1.07); and the genotypic frequency in the group of cases was: 0.65 for homozygotes F(176)/F(176), 0.30 for heterozygotes and 0.05 for the homozygotes V(176)/V(176), while for the control group it was 0.53, 0.39 and 0.08, respectively. The polymorphism FCGR3A V(176) is not associated with SLE or any of its manifestations in patients with SLE from the West of Mexico.     

Fcgamma receptor IIIA polymorphism as a risk factor for acute poliomyelitis

Poliomyelitis is a viral infection that causes flaccid paralysis in approximately 1% of cases. The Fc receptors for immunoglobulin G (FcgammaR) are associated with modifying effects of several infectious and autoimmune diseases. To assess the influence of FcgammaR polymorphisms on the acute and late course of poliomyelitis, 110 Norwegian patients with well-defined histories of acute poliomyelitis were genotyped, of whom 50 suffered from the postpolio syndrome (PPS). In comparison with healthy control subjects without a history of poliomyelitis, significantly fewer patients had the FcgammaRIIIA genotype V/V (P<.01). However, this genotype was not an independent risk factor for PPS. The FcgammaRIIA and IIIB genotypes and allele frequencies did not differ between the patients and control subjects. The FcgammaRIIIA V/V genotype may lower the risk for contracting acute poliomyelitis through better clearance of poliovirus.     

Association of ACE gene polymorphism with genetic susceptibility to systemic lupus erythematosus in a Chinese population: a family-based association study

OBJECTIVE: Family-based association analysis was performed to investigate whether the angiotensin-converting enzyme (ACE)-G261T and ACE-A592G polymorphisms are risk factors for systemic lupus erythematosus (SLE) in a Chinese population. METHODS: A total of 119 patients with SLE from 95 nuclear families, aged from 14 to 78 years, who met the American College of Rheumatology 1997 criteria, were recruited, as were 316 family members of these patients. A family-based association study was used to explore the association between ACE gene polymorphisms (ACE-G261T and ACE-A592G) and SLE. The ACE gene polymorphisms were genotyped with restriction fragment length polymorphism-polymerase chain reaction. RESULTS: Using family-based association tests, the T allele of the ACE-G261T single-nucleotide polymorphism (SNP) was significantly associated with genetic susceptibility to SLE in an additive model (Z = 2.877, p = 0.004), a dominant model (Z = 2.557, p = 0.011), and a recessive model (Z = 2.202, p = 0.028). No association between the ACE-A592G SNP and SLE susceptibility was determined. CONCLUSION: The T allele of the ACE-G261T SNP was associated with SLE in this Chinese population.     

Vitamin D receptor gene BsmI polymorphism B allele, but not BB genotype, is associated with systemic lupus erythematosus in a Han Chinese population

The vitamin D receptor (VDR) gene is a candidate gene for susceptibility to autoimmune disorders. Association studies of VDR polymorphisms and risk of systemic lupus erythematosus (SLE) have often produced conflicting results in different ethnic backgrounds. The aim of this study is to test the association between VDR gene BsmI polymorphism and the genetic susceptibility to SLE in a Han Chinese population. Three hundred and thirty-seven patients with SLE and 239 healthy controls were genotyped for the VDR gene BsmI polymorphism (rs1544410) by polymerase chain reaction and restriction fragment length polymorphism analysis in this study, after which the relationship between BsmI polymorphisms and the mRNA expression of VDR, as well as clinical manifestations in patients with SLE, was evaluated. It was found that the frequency of B allele was significantly increased in SLE relative to the control group (χ(2)?=?4.681, p?=?0.031), although the distribution of VDR BsmI polymorphism genotype frequencies did not differ significantly between patients and controls (χ(2)?=?4.098, p?=?0.129). Moreover, VDR B allele was found to be associated with lupus nephritis (p?=?0.027) and also with production of anti-nucleosome antibodies (p?=?0.037). The mRNA of VDR was markedly down-regulated in patients with VDR B allele compared with that in patients without B allele (p?=?0.016). Our results indicate a possible role of genetic factors (the VDR B allele) in influencing disease susceptibility in Han Chinese patients. Also, VDR B allele is associated with the development of nephritis and the down-regulation of VDR mRNA expression in SLE.     

Absence of association between the Fc gamma receptor IIIA-176F/V polymorphism and the severity of malaria in Thai

Human Fc gamma receptor (Fc gamma R) genes form a clustered gene family, which consists of Fc gamma RIIA, IIB, IIC, IIIA, and IIIB genes, on chromosome 1q23. We previously reported that the Fc gamma RIIA-131H/H genotype in combination with the Fc gamma RIIIB-NA2 allele is associated with susceptibility to cerebral malaria, and that such an association can be caused by linkage disequilibrium (LD) between these polymorphisms and the primary associated gene(s) in this region. Fc gamma RIIIA is known to exhibit the genetic polymorphism Fc gamma RIIIA-176F/V coded for different affinity to IgG1 and IgG3. In this study, we examined a possible association between Fc gamma RIIIA-176F/V polymorphism and severity of malaria in 462 adult Thai patients with Plasmodium falciparum malaria. The frequencies of Fc gamma RIIIA-176V among patients with mild malaria, with non-cerebral severe malaria, and with cerebral malaria were 32.7%, 29.9%, and 36.3%, respectively. This polymorphism showed neither positive nor negative association with the severity of malaria. Thus, we concluded that the association of Fc gamma RIIA-131H/R and Fc gamma RIIIB-NA1/NA2 polymorphisms with cerebral malaria in Thailand is not due to the LD caused by Fc gamma RIIIA-176F/V.     

Polymorphisms in inflammatory cytokines and Fcgamma receptors in childhood chronic immune thrombocytopenic purpura: a pilot study

Inflammatory cytokines and low-affinity Fcgamma receptor (FcgammaR) polymorphisms were investigated in 37 children with chronic immune thrombocytopenic purpura (cITP) and 218 controls. Genotype analysis included common variants in the regulatory regions of cytokines, TNF, LTA, IL1RN, IL1A, IL1B, IL4, IL6 and IL10, and structural variants of the low affinity FcgammaRs, FCGR2A, FCGR3A and FCGR3B. Associations were observed for TNF (P = 0.0032), LTA (P = 0.019), FCGR3A (P = 0.038) and FCGR3B (P = 0.0034). Two combinations of genotypes (TNF and FCGR3A; P = 0.0003, and LTA and FCGR3B; P = 0.011) were significantly associated with cITP. These results provide preliminary evidence that variant genotypes of FcgammaRs and cytokines contribute to cITP pathogenesis.     

Fc γ R IIIB polymorphisms: their association with clinical manifestations and autoantibodies in SLE patients from Western India

Background: Receptors for the Fc fragment of immunoglobulin G (Fc γ Rs) represent the link between the humoral and cellular immune responses. Polymorphisms of Fc γ R, mainly IIA, IIB, IIIA, IIIB have been identified as genetic factors influencing susceptibility to disease or disease course of a prototype autoimmune disease like systemic lupus erythematosus (SLE). Fc γ alleles may be associated with inefficient removal of apoptotic cells or antigens and hence may be associated with higher risk of SLE. Objective: This study was designed to look for Fc γ RIIIB polymorphisms of three different alleles, NA1, NA2 and SH in SLE patients and to correlate the distribution of Fc γ RIIIB genotypes with clinical presentation and autoantibody profile. Material and methods: Eighty SLE patients along with eighty normal individuals were studied. Fc γ RIIIB polymorphism was tested by allele‐specific primer amplification. Results: The percentage distribution of NA1/NA1, NA1/NA2 and NA2/NA2 was 22.5%, 40% and 37.5%, respectively, among the normal population; and among SLE patients it was 25%, 40% and 35%, respectively. The percentage distribution of SH allele was 68.8% among the normal population, while in SLE patients it was 60%. No statistical difference was found in the distribution of Fc γ R IIIB genotypes in patients of lupus nephritis and SLE without nephritis (P > 0.05). Conclusion: Among SLE patients studied, NA2 was the prominent allele. It was commonly associated with clinical manifestations such as skin rash, arthritis, hematological and immunological disorders. This suggests that the primary involvement of Fc γ R IIIB NA2 allele is more likely involved with disease susceptibility of SLE.     

Low-binding alleles of Fcgamma receptor types IIA and IIIA are inherited independently and are associated with systemic lupus erythematosus in Hispanic patients

OBJECTIVE: To examine the relationship between allelic polymorphisms of IgG receptors (FcgammaR) and the development of lupus nephritis in a prospective study, and to determine the distribution of FcgammaR haplotypes (FcgammaRIIA and FcgammaRIIIA genotypes) in lupus patients and disease-free control subjects. METHODS: We studied 67 Hispanic systemic lupus erythematosus (SLE) patients from a prospective study of outcome and 53 disease-free control subjects. Patients were followed up longitudinally for 3 years. FcgammaRIIA and FcgammaRIIIA genotypes were determined using allele-specific polymerase chain reaction. RESULTS: Nephritis was present in 28% of patients at entry into the study and in 69% at the end of 3 years. In the nephritis group (n = 46), as well as the entire SLE cohort, there was a predominance of genotypes with low-binding alleles (FcgammaRIIa-R131 and FcgammaRIIIa-F176) at both loci (SLE nephritis patients 89% versus controls 62%; P < 0.002; odds ratio 0.20 [95% confidence interval 0.05-0.6] for risk of nephritis in individuals homozygous for either FcgammaRIIa-H131 or FcgammaRIIIaV176). The frequency of individuals homozygous for high-binding alleles at either locus decreased as the burden of disease increased (P < 0.002, by Mann-Whitney test). There was no linkage disequilibrium between FcgammaRIIA and FcgammaRIIIA in Hispanics, yet in the SLE patients, there was a clear overrepresentation of the FcgammaRIIa-R131;FcgammaRIIIa-F176 haplotype (SLE patients 48% versus controls 30%) and a decrease in the frequency of the high-binding haplotype (4% versus 23%) (P < 0.002). CONCLUSION: We observed an increase in the frequency of low-binding FcgammaR alleles in an SLE population with a high prevalence of renal disease. The apparent selection for the FcgammaRIIa-R131;FcgammaRIIIa-F176 haplotype in Hispanic patients suggests that low-binding alleles of both FcgammaRIIa and FcgammaRIIIa confer risk for SLE and may act additively in the pathogenesis of disease, whereas the high-binding haplotype FcgammaRIIa-H131;FcgammaRIIIa-V176 is protective, particularly in the homozygous state.     

Analysis of polymorphisms affecting immune complex handling in systemic lupus erythematosus

OBJECTIVES: Systemic lupus erythematosus (SLE) is a polygenic disorder of dysregulated inflammation. Numerous specific candidate genes have been identified and most relate to the handling of immune complexes or antigen presentation. This is consistent with the classic finding of immune complex deposition in affected end organs. We wished to examine combinatorial effects of polymorphic variants of genes involved in immune complex clearance in susceptibility to lupus. METHODS: This study examined the occurrence of polymorphisms in genes which encode proteins known to be involved in immune complex handling and clearance. Each polymorphic variant of a complement protein (C2, mannose binding protein and C4), complement receptor (CR1) or Fc receptor (FcgammaRIIA and FcgammaRIIIA) gene is known to affect function adversely. One hundred and sixty SLE patients and 212 control subjects were genotyped using polymerase chain reaction methods. RESULTS: We found an increasing association of SLE with increasing numbers of gene defects. Combinations of severe defects in FcgammaRIIA and FcgammaRIIIA were particularly deleterious for both African American and Caucasian patients, even though only one defective variant was individually statistically significantly associated with SLE. CONCLUSIONS: The results of the study suggest that genes may interact in ways that either synergize or modify the effect of a single genetic effect and imply that association studies must be interpreted within the genetic background of the populations.     

Fcgamma receptor IIa,IIIa, and IIIb polymorphisms in German patients with systemic lupus erythematosus: association with clinical symptoms

BACKGROUND: Receptors for IgG play an important part in immune complex clearance. Several studies have identified polymorphisms of receptors for the Fc fragment of IgG (FcgammaR) as genetic factors influencing susceptibility to disease or disease course of systemic lupus erythematosus (SLE). OBJECTIVE: To examine these possibilities by evaluating a panel of clinical parameters in a cohort of 140 German patients with SLE for correlations with the FcgammaRIIa, IIIa, and IIIb polymorphisms in an explorative study. METHODS: 140 German patients with SLE according to American College of Rheumatology (ACR) criteria and 187 German controls were genotyped for the FcgammaRIIa, IIIa, and IIIb polymorphisms. Associations between FcgammaR genotypes, combined genotypes and clinical as well as laboratory features were analysed. RESULTS: No significant skewing of any of the three FcgammaR polymorphisms was seen in the German SLE cohort studied. Various clinical and serological parameters were found more frequently and at younger age in homozygous patients with the genotypes IIA-R/R131 or IIIA-F/F158 than in patients with IIA-H/H131 or IIIA-V/V158. These effects were even more pronounced in patients with the low binding combined phenotypes of the FcgammaRIIa, IIIa (double negative phenotypes) and FcgammaRIIa, IIIa, and IIIb (triple negative phenotypes). In patients with the double negative IIA and IIIA genotypes significantly higher frequencies of nephritis (63% v 33%) and proteinuria according to ACR criteria (58% v 11%), anaemia (84% v 55%), and anticardiolipin antibodies (63% v 22%) were found than in patients with the double positive genotypes. Patients with the IIA-R/R131 genotype and the double negative homozygous genotype had an earlier incidence of clinical symptoms, haematological and immunological abnormalities. Accordingly, SLE is diagnosed earlier in these patients, the difference reaching statistical significance only in the double negative v the double positive genotype (26.3 v 39.5 years) and the IIIA-F/F158 genotype v the rest (26.7 v 32.0 years). Most relevant is the fact that a higher median disease activity (ECLAM score) was demonstrated, both in the IIA-R/R131 homozygous (3.3 v 2.7) and the double negative (3.4 v 2.3) patients, reaching statistical significance in the first group. CONCLUSION: The results of this explorative study support the view that the FcgammaRIIa/IIIa and IIIb polymorphisms constitute factors influencing clinical manifestations and the disease course of SLE but do not represent genetic risk factors for the occurrence of SLE. Higher frequencies of clinical symptoms, haematological and immunological abnormalities as well as an earlier onset of clinical symptoms, haematological and immunological markers of active disease were found in patients with the IIA-R/R131 genotype and the double negative and triple negative genotypes.     

FcgammaRIIa polymorphism in Japanese patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an immune complex-mediated disease and organ damage is caused by the deposition of immune complex. Receptors which recognize the Fc portion of immunoglobulin G (FcgammaR) play a key role in the phagocytosis of immune complexes. As the gene encoding for FcgammaR of class IIa (FcgammaRIIa) has two allelic forms, H131 and R131, which differ in their affinity to IgG2, this polymorphism might have implications in handling immune complex. We studied the distribution of the FcgammaRIIa polymorphism in 90 Japanese patients with SLE. We also examined the association between FcgammaRIIa polymorphism and the disease activity of SLE and the histopathological findings of lupus nephritis. FcgammaRIIa polymorphism was determined by PCR and dot blot analysis. The allelic frequency of H131 in patients with SLE was significantly lower (H131/R131 = 0.44/0.56) than that of normal controls (H131/R131 = 0.62/0.38; P < 0.05). No significant association was observed between FcgammaRIIa polymorphism and the clinical parameters for the activity of SLE. There was no association between FcgammaRIIa polymorphism and the histological findings in lupus nephritis. The difference in the distribution of FcgammaRIIa alleles between patients with SLE and normal subjects indicates that this polymorphism is a candidate of susceptibility gene for SLE in Japanese.