Independent association of HLA-DR and FCgamma receptor polymorphisms in Korean patients with systemic lupus erythematosus

OBJECTIVES: To determine the distribution of HLA-DR type and FcgammaRIIa/IIIa polymorphisms, and to analyse the combined effects of these genes for susceptibility in Korean systemic lupus erythematosus (SLE) patients. METHODS: A total of 299 SLE patients meeting 1982 ACR criteria and 144 Korean disease-free controls were enrolled. Genotyping for the FcgammaRIIa 131 R/H and FcgammaRIIIa 176 F/V was performed by polymerase chain reaction (PCR) of genomic DNA using allele-specific primers. HLA-DRB1 typing was performed by the PCR-SSOP method. RESULTS: There was significant skewing in the distribution of the three FcgammaRIIa genotypes between the SLE patients and the controls [P = 0.002 for R/R131 vs R/H131 and H/H131, relative risk (RR) 2.6 (95% CI 1.3-5.2)], but not in FcgammaRIIIa genotypes. HLA-DRB1*15 allele was significantly more prevalent among SLE patients than the control population [P < 0.02, RR = 1.7 (1.1-2.6)]. HLA-DRB1 genotypes or allele frequencies of the SLE patients with nephritis did not differ significantly from those of the SLE patients without nephritis. We analysed the combined effects of the two candidate genes on SLE susceptibility. HLA-DRB1*15 allele was a significant predictor of SLE in individuals who were not homozygous for FcgammaRIIa-R/R131 [RR = 2.1 (1.2-3.7), P < 0.008], and the FcgammaRIIa-R/R131 genotype vice versa [RR = 5.3 (1.9-15.4), P < 0.001]. However, an additive or synergistic effect of both susceptible genes on relative risk for SLE was not evident. CONCLUSIONS: Our results suggest that FcgammaRIIa-R/R131 homozygote and HLA-DRB1*15 allele are independent risk factors in Korean SLE patients without additive or synergistic effects.     

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.     

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.     

Role of the Fcgamma receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis

OBJECTIVE: To assess the impact of the Fcgamma receptor type IIa (FcgammaRIIa)-R/H131 polymorphism on the risk for systemic lupus erythematosus (SLE) and development of lupus nephritis. METHODS: A meta-analysis was performed based on the Medline and Embase databases (last retrieval August 2001), assessment of bibliographies of pertinent articles, and additional data gathered after contact with primary investigators. RESULTS: A total of 25 comparisons from 17 studies involving R/H131 genotyping of 1,405 patients with lupus nephritis, 1,709 SLE patients without nephritis, and 2,580 non-SLE controls were included. No association between RR genotype and risk of lupus nephritis relative to both other genotypes (odds ratio [OR] 1.05, 95% confidence interval [95% CI] 0.88-1.27) was demonstrated in the total meta-analysis or in any racial subgroup. The RR genotype was more frequent in SLE patients as a whole (OR 1.30, 95% CI 1.10-1.52) and in SLE patients without nephritis (OR 1.27, 95% CI 1.04-1.55) compared with disease-free controls. A potential dose-response relation between the R131 allele and the risk of SLE was also identified, with an OR of 1.23 for RR versus RH (95% CI 1.03-1.46). The OR was 1.55 for RR versus HH (95% CI 1.21-1.98). There was no significant heterogeneity between racial subgroups. The population-attributable fractions of SLE cases due to the FcgammaRIIa-R131 allele were 13%, 40%, and 24% in subjects of European, African, and Asian descent, respectively. CONCLUSION: The FcgammaRIIa-R/H131 polymorphism represents a significant risk factor for SLE but has no clear effect on susceptibility for lupus nephritis.     

Association between SLE nephritis and polymorphic variants of the CRP and FcgammaRIIIa genes

OBJECTIVES: To study the relationship between clinical manifestations in systemic lupus erythematosus (SLE) with polymorphisms in suggested susceptibility genes encoding FcgammaRIIa, FcgammaRIIIa, FcgammaRIIIb, CRP and IL-1Ra. METHODS: Genetic polymorphisms were analysed in 323 unrelated SLE patients and 200 healthy blood donors. The genotype frequencies were compared between clinical subsets of SLE patients, as well as with healthy controls. Clinical manifestations included the ACR classification criteria. Nephritis was further classified according to WHO class on renal biopsy. RESULTS: Presence of a CRP4 A-allele was associated with SLE nephritis (P < 0.01) and inversely correlated with arthritis (P < 0.01), when comparing within the SLE group. The FcgammaRIIIa F/F genotype was also associated with nephritis (WHO class III and IV, P = 0.04 for the SLE group) and in combination with the CRP4 A-allele a stronger association was noted (P < 0.001). Furthermore, the FcgammaRIIIb NA2/NA2 genotype was associated with butterfly rash (P < 0.01). An association was found between seizures and the presence of both the FcgammaRIIa R/R and the FcgammaRIIIa F/F genotypes (P < 0.01) and an inverse correlation between serositis and the CRP4 A-allele when present together with the IL-1Ra 2-allele (P = 0.01). Furthermore, a combination of the FcgammaRIIa R/R genotype and CRP4 A-allele was associated with lymphopenia (P = 0.02) and a similar result was found for the combination of FcgammaRIIIa F/F and FcgammaRIIIb NA2/NA2 (P = 0.04). CONCLUSIONS: Polymorphic variants of the CRP and Fcgamma-receptor genes are associated with the clinical phenotype in SLE. Our findings suggest an immune complex-mediated pathogenesis in nephritis and seizures, while development of arthritis may depend on other pathogenetic pathways.     

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.     

Identification of IgG subclasses and C-reactive protein in lupus nephritis: the relationship between the composition of immune deposits and FCgamma receptor type IIA alleles

OBJECTIVE: To characterize the subclass composition of IgG deposited in lupus glomeruli, to examine its relationship to allelic polymorphisms of IgG receptors (Fcgamma receptors [FcgammaR]), and to determine whether C-reactive protein (CRP), a ligand for FcgammaRIIa, is present in these immune deposits. METHODS: Renal biopsy samples from 80 patients with lupus nephritis were examined by light microscopy and indirect immunofluorescence with IgG-subclass-specific monoclonal antibodies. FcgammaRIIA genotypes were determined using allele-specific polymerase chain reaction. Immunostaining for CRP was performed on lupus and nonlupus glomerulonephritis specimens. RESULTS: IgG2 and IgG3 were the predominant subclasses in immune deposits in all World Health Organization classes of nephritis. The frequency of genotypes containing the low-binding IgG2 allele, FcgammaRIIa-R131, was significantly greater than expected in patients with class III or class IV nephritis and in patients with intense IgG2 deposition. CRP, a ligand with particular affinity for FcgammaRIIa-R131, was consistently present in the renal immune deposits of lupus nephritis specimens. CONCLUSION: FcgammaRIIA genes are associated with proliferative renal disease and may contribute to disease pathogenesis. FcgammaRIIa-R131, the variant with low affinity for IgG2, has high affinity for CRP. Thus, FcgammaRIIa-R131 may contribute to impaired removal of circulating immune complexes, as well as efficiently triggering phagocyte activation and the release of inflammatory mediators within glomeruli.     

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.     

Role of the Fcγ receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: A meta‐analysis

Objective

To assess the impact of the Fcγ receptor type IIa (FcγRIIa)–R/H131 polymorphism on the risk for systemic lupus erythematosus (SLE) and development of lupus nephritis.

Methods

A meta‐analysis was performed based on the Medline and Embase databases (last retrieval August 2001), assessment of bibliographies of pertinent articles, and additional data gathered after contact with primary investigators.

Results

A total of 25 comparisons from 17 studies involving R/H131 genotyping of 1,405 patients with lupus nephritis, 1,709 SLE patients without nephritis, and 2,580 non‐SLE controls were included. No association between RR genotype and risk of lupus nephritis relative to both other genotypes (odds ratio [OR] 1.05, 95% confidence interval [95% CI] 0.88–1.27) was demonstrated in the total meta‐analysis or in any racial subgroup. The RR genotype was more frequent in SLE patients as a whole (OR 1.30, 95% CI 1.10–1.52) and in SLE patients without nephritis (OR 1.27, 95% CI 1.04–1.55) compared with disease‐free controls. A potential dose–response relation between the R131 allele and the risk of SLE was also identified, with an OR of 1.23 for RR versus RH (95% CI 1.03–1.46). The OR was 1.55 for RR versus HH (95% CI 1.21–1.98). There was no significant heterogeneity between racial subgroups. The population‐attributable fractions of SLE cases due to the FcγRIIa‐R131 allele were 13%, 40%, and 24% in subjects of European, African, and Asian descent, respectively.

Conclusion

The FcγRIIa‐R/H131 polymorphism represents a significant risk factor for SLE but has no clear effect on susceptibility for lupus nephritis.

     

Relevance of Fcgamma receptor and interleukin-10 polymorphisms for meningococcal disease.

The contribution of individual Fcgamma receptor (FcgammaR) subclasses to meningococcal phagocytosis was studied. In addition, functional FcgammaR polymorphisms were determined in 50 patients with meningococcal disease (MD), in 183 first-degree relatives of MD patients, and in 239 healthy control subjects, to study the association of FcgammaR genotypes with disease. Efficient internalization of opsonized Neisseria meningitidis serogroup B was mediated via multiple FcgammaR subclasses on phagocytes. Accordingly, a low-efficiency combination of FcgammaRIIa-R/R131, FcgammaRIIIa-F/F158, and FcgammaRIIIb-NA2/2 genotypes was increased significantly in relatives of patients with MD, compared with healthy control subjects (P<.05; odds ratio, 2.6; 95% confidence interval, 1.1-6.3). FcgammaRIIa and FcgammaRIIIa genotype distributions differed between patients with sepsis and those with meningitis. Combined genotypes of FcgammaRIIa and interleukin-10 -1082, which was previously reported as being associated with MD outcome, were distributed randomly in control subjects but not in relatives of patients with MD (P<.01). These data provide further evidence for the association of polymorphic genes on chromosome 1 and MD.     

Low‐binding alleles of Fcγ 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 (FcγR) and the development of lupus nephritis in a prospective study, and to determine the distribution of FcγR haplotypes (FcγRIIA and FcγRIIIA 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. FcγRIIA and FcγRIIIA 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 (FcγRIIa‐R131 and FcγRIIIa‐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 FcγRIIa‐H131 or FcγRIIIa‐V176). 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 FcγRIIA and FcγRIIIA in Hispanics, yet in the SLE patients, there was a clear overrepresentation of the FcγRIIa‐R131;FcγRIIIa‐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 FcγR alleles in an SLE population with a high prevalence of renal disease. The apparent selection for the FcγRIIa‐R131;FcγRIIIa‐F176 haplotype in Hispanic patients suggests that low‐binding alleles of both FcγRIIa and FcγRIIIa confer risk for SLE and may act additively in the pathogenesis of disease, whereas the high‐binding haplotype FcγRIIa‐H131;FcγRIIIa‐V176 is protective, particularly in the homozygous state.

     

Fcgamma receptor IIa, IIIa, and IIIb polymorphisms of systemic lupus erythematosus in Taiwan

OBJECTIVE: To determine whether the distribution of Fcgamma receptor IIa, IIIa, and IIIb polymorphisms confers a risk factor for disease susceptibility, and correlates with the clinical characteristics and serological parameters of patients with SLE in Taiwan. METHODS: Genotyping of Fcgamma receptors IIa H/R131, IIIa F/V158, and IIIb NA1/NA2 was performed in 302 patients with SLE and 311 healthy blood donor controls. The distribution of Fcgamma receptor IIa, IIIa, and IIIb genotypes in patients and controls was analysed. Frequencies of three Fcgamma receptor polymorphisms were also compared between lupus patients with and without different clinical manifestations and autoantibodies. RESULTS: No significant skewing in the distribution of Fcgamma RIIa H/R131, Fcgamma RIIIa F/V158, and Fcgamma RIIIb NA1/NA2 was found between patients and controls in Taiwan. The following clinical associations were found: Fcgamma RIIIb NA1/NA1 protected against neuropsychiatric lupus (p = 0.028) but conferred susceptibility to discoid rash (p<0.005); increased Fcgamma RIIIa V/V158 was associated with infections (p = 0.039); increased Fcgamma RIIa H/H131 was associated with earlier onset of lupus (p = 0.01). CONCLUSION: Fcgamma receptor IIa, IIIa, and IIIb polymorphisms may be responsible for the development of distinct manifestations of lupus patients in Taiwan, but there is no significantly skewed distribution in the susceptibility to lupus as a whole.     

Polymorphism of the FcgammaRIIalpha IgG receptor in patients with lupus nephritis and glomerulopathy

OBJECTIVE: FcgammaRIIalpha is a low affinity receptor that has 2 codominantly expressed alleles, R131 and H131, which differ in their ability to bind immunoglobulin G (IgG) subclasses. Cells expressing H131 bind more efficiently complexed IgG2 than those expressing the R131 variant. The FcgammaRIIalpha polymorphism has been shown to be associated with lupus nephritis. We evaluated the relevance of FcgammaRIIalpha gene polymorphism in the development of lupus immune complex mediated nephritis, as well as its clinical and histological characteristics, by comparing the genotype and allelic distribution of this receptor in lupus nephritis to ethnically matched Brazilian patients with primary glomerulonephritis. METHODS: Patients with lupus nephritis (n = 76) and patients with diagnosis of primary glomerulonephritis (n = 63) established by kidney biopsies were recruited. FcgammaRIIalpha genotyping was performed by polymerase chain reaction with allele-specific primers to distinguish between the 2 allelic forms (H131 and R131). RESULTS: We observed a skewed frequency of genotype FcgammaRIIalpha-R/R131 and the R131 allele in patients with lupus nephritis compared to primary glomerulopathies (p < 0.05), which disappeared when we compared this population with lupus nephritis only to the group with proliferative glomerulonephritis (IgA nephropathy, membranoproliferative glomerulonephritis, and mesangial proliferative glomerulonephritis). No association was found between genotype distribution and histological class of lupus nephritis or renal insufficiency available at the beginning and end of followup. We found an association of genotype FcgammaRIIalpha-R/R131 with higher antinuclear antigen titers and complement 3 consumption (p < 0.05). CONCLUSION: The skewed distribution of FcgammaRIIalpha genotypes with the predominance of homozygous R/R131 genotype observed in patients with lupus nephritis over nonproliferative idiopathic glomerulonephritis emphasizes its importance as a heritable risk factor for immune complex mediated renal injury in Brazilian patients with lupus.     

Skewed distribution of IGG FC receptor iia (CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients

Objective. Fcγ receptors of class IIa (FcγRIIa) occur in 2 allelic forms, with either a low (IIa-R131) or a high (IIa-H131) affinity for complexed IgG2 and IgG3. This polymorphism might have implications for the handling of immune complexes. Therefore, we determined the distribution of the Fc γRIIa allotypes in patients with systemic lupus erythematosus (SLE), with or without a history of lupus nephritis. Methods. We studied 95 unrelated white European patients with SLE, as defined by the American College of Rheumatology criteria, 50 of whom had a history of lupus nephritis, and 69 healthy white European control subjects. Fc γRIIa allotypes were determined by immunophenotyping of blood monocytes. Results. It was found that lupus nephritis was significantly associated with the ‘low affinity’ FcγRIIa R/R131 allotype and with the R131 allele, compared with healthy controls. No significant association was found upon comparison of groups with and without nephritis. Conclusion. SLE patients with a history of lupus nephritis have an abnormal distribution of FcγRIIa allotypes. FcγRIIa may well play a role in the pathogenesis of lupus nephritis, since IIa-R/R131 SLE patients seem to have a higher incidence of developing this complication.     

The association between fcgammaRIIIB polymorphisms and systemic lupus erythematosus in Korea

Polymorphisms of FcgammaR have been proposed as genetic factors that influence susceptibility to SLE. FcgammaRIIIB polymorphism in systemic lupus erythematosus (SLE) have been studied in various populations, but the results were inconsistent. The aim of this study was to determine the association of FcgammaRIIIB polymorphism in Korean lupus patients. One-hundred and eighty-three SLE patients (166 female, 17 male) meeting 1982 ACR criteria and 300 Korean disease-free controls were enrolled. Genotyping for the FcgammaRIIIB NA1/NA2 was performed by PCR of genomic DNA using allele-specific primers. There was no significant skewing in the distribution of the three FcgammaRIIIB genotypes, and alleles between SLE and the controls. The frequency of FcgammaRIIIB genotypes in SLE patients and controls was FcgammaRIIIB NA1/NA1 27.9% versus 26%, NA1/NA2 55.2% versus 51.7%, NA2/NA2 16.9% versus 22.3%, respectively. The gene frequencies of NA1 allele were 0.56 in the SLE and 0.52 in controls, respectively. Among clinical manifestations, thrombocytopenia was more common in FcgammaRIIIB NA2/NA2 genotype (P = 0.04, OR 2.4, 95% CI 1.0-5.4), and NA2 allele (P = 0.03, OR 1.7, 95% CI 1.1-2.8). Although FcgammaRIIIB polymorphism was not associated with the development of SLE in Korean, thrombocytopenia was associated with FcgammaRIIIB NA2/NA2 genotype, and NA2 allele.     

Fcgamma receptor polymorphisms in Wegener's granulomatosis: risk factors for disease relapse.

OBJECTIVE: Several studies have recently identified polymorphisms of receptors for the Fc fragment of IgG (FcgammaR) as genetic factors influencing susceptibility to multiple autoimmune and infectious diseases. This genetic predisposition could also influence the expression of Wegener's granulomatosis (WG), a systemic autoimmune disease with chronic nasal carriage of Staphylococcus aureus as an important risk factor for disease relapses. Therefore, we analyzed 3 functional FcgammaR polymorphisms from 91 patients with WG and 154 controls for a possible relationship with disease expression and occurrence of relapses. METHODS: FcgammaR phenotypes were determined using amplification of FcgammaR-genomic regions in allotype-specific polymerase chain reactions. Of particular interest in the analysis were 2 allotypic forms of FcgammaRIIa (R131 or H131) and 2 allotypic forms of FcgammaRIIIa (V158 or F158), all of which are functionally different. RESULTS: Analysis of FcgammaR phenotypes demonstrated that patients with WG were more prone to disease relapse in the first 5 years after diagnosis if they were homozygous for both the R131 form of FcgammaRIIa and the F158 form of FcgammaRIIIa (relative risk 3.3, 95% confidence interval 1.6-6.8). These polymorphisms are both associated with decreased FcR-mediated clearance, which may be relevant to the chronic nasal carriage of S aureus. CONCLUSION: Both the R/H131 polymorphism of FcgammaRIIa and the V/F158 polymorphism of FcgammaRIIIa represent heritable risk factors for the development of disease relapses in WG.     

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.     

The homozygous FcgammaRIIIa-158V genotype is a risk factor for heparin-induced thrombocytopenia in patients with antibodies to heparin-platelet factor 4 complexes

We hypothesized that Fcgamma receptor IIIa (FcgammaRIIIa), a polymorphic receptor for the Fc portion of immunoglobulin G (IgG) other than FcgammaRIIa, was involved in heparin-induced thrombocytopenia (HIT). FcgammaRIIa-131 and FcgammaRIIIa-158 genotypes were determined in 102 patients with definite HIT and in 2 control groups of patients treated by heparin (86 subjects without detectable antibodies [Abs] to heparin-platelet factor 4 [H/PF4], Ab(-) group; 84 patients with Abs to H/PF4 without HIT, Ab(+) group). There were no significant differences in genotype distribution or allele frequencies between the 3 groups for FcgammaRIIa-131H/R polymorphism. In contrast, FcgammaRIIIa-158V homozygotes were more frequent in the HIT group than in the Ab(+) group (P = .02), a difference that was more pronounced in patients with high levels of anti-H/PF4 Abs (P = .01). Since anti-H/PF4 Abs are mainly IgG1 and IgG3, clearance of sensitized platelets may be increased in patients homozygous for the FcgammaRIIIa-158V allotype, thus contributing to the development of thrombocytopenia.     

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。     

Angiotensin-converting enzyme gene polymorphism and vascular manifestations in Korean patients with SLE

Systemic lupus erythematosus (SLE) is an inflammatory multisystem disease of unknown etiology with immunologic aberrations. Many studies have shown that genetic and environmental factors are implicated in the development of SLE. Angiotensin-converting enzyme (ACE) affects various immune phenomena through the renin-angiotensin and kallikrein-kininogen systems by creating angiotensin II and inactivating bradykinin. We investigated the correlation between insertion/ deletion polymorphism of the ACE gene and the clinical manifestations of SLE, especially vascular involvement and lupus nephritis. Two-hundred and eleven Korean patients fulfilling the ACR criteria and 114 healthy subjects were enrolled. The ACE genotype was determined by polymerase chain reaction using genomic DNA from peripheral blood. The nephritis patients were classified by the WHO classification. In addition, the activity and chronicity index were used to assess the severity of renal involvement. We evaluated vascular involvement by the presence or absence of hypertension, Raynaud's phenomenon, livedo reticularis, antineutrophil cytoplasmic antibody and the SLICC/ACR Damage Index. The gene frequency of ACE gene polymorphism was as follows: II 39 vs 34%, ID 41 vs 50%, DD 20 vs 16% in SLE patients and controls, respectively. There was no difference in genotype frequency between both groups. There were no significant differences between the distribution of ACE gene genotypes and lupus nephritis and its related parameters, including WHO classification, activity index, chronicity index, renal dysfunction and amount of 24 h urinary protein. The ACE genotypes and alleles did not affect the presence of vascular manifestations evaluated, but the frequency of DD genotype was significantly low in SLE patients with Raynaud's phenomenon compared to those without Raynaud's phenomenon (P = 0.002 for ACE ID vs DD and II, OR 2.7, 95% CI 1.43-5.09; P=0.023 for ACE DD vs ID and II, OR 0.33, 95% CI 0.12-0.89). Also skewing from DD to II genotype was noted in patients with anti-Sm antibody compared to those without anti-Sm antibody (P = 0.025 for ACE DD vs ID and II, OR 0.21, 95% CI 0.05-0.93). The onset age of serositis was older in patients with the ID genotype than the others (ID= 34.5+/-10.8, II + DD = 25.6+/-10.2, P= 0.002). Also the onset age of malar rash was older in patients with II genotype than the others (II=26.7+/-8.4, ID+DD=21.3+/-9.0; P=0.021). The patients with I allele showed a significantly higher frequency of serositis (P = 0.022). Taken together, the I/D polymorphisms of ACE gene did not affect susceptibility of SLE, lupus nephritis and the vascular manifestations, including Raynaud's phenomenon, in Korean SLE patients, although the DD genotype was negatively associated with Raynaud's phenomenon among SLE patients. However, it would be valuable to evaluate the role of other genes potentially related to vascular events, such as endothelin, nitric oxide or angiotensin II receptor as well as ACE gene.