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.     

FcγRIIa polymorphism in systemic lupus erythematosus

OBJECTIVES—Polymorphism of the phagocyte IgG receptor FcγRIIa may modulate immune complex mediated inflammation, particularly when immune complexes contain IgG2. Previous studies suggest that this polymorphism may be an important risk factor for lupus nephritis. FcγRIIa is biallelic, the alleles R and H each having a gene frequency of about 50%. Nephritis has been associated with an increased frequency of the R allele. The frequency of common FcγRIIa alleles was examined in white subjects from the United Kingdom and Greek subjects with systemic lupus erythematosus (SLE) and healthy controls.
METHODS—FcγRIIa genotyping was performed using a single step polymerase chain reaction technique, which differentiates the two major alleles, R and H. Two study populations were examined: (a) white subjects from the United Kingdom : 66 controls and 81 with SLE (19 of whom had renal disease) and (b) Greek: 52 controls and 42 with SLE (19 with renal disease).
RESULTS—No significant relation was observed between FcγRIIa genotype and susceptibility to SLE or SLE nephritis.
CONCLUSIONS—The FcγRIIa R allele does not seem to be associated with SLE (with or without renal disease) in our United Kingdom white or Greek populations.

     

Fcγ receptor biology and systemic lupus erythematosus

The maintenance of immune homeostasis and the regulation of pro‐inflammatory responses that underlie autoimmune pathology require a coordinated interplay between cytokines, cellular receptors and downstream signaling pathways. The family of fragment crystallizable receptors for immunoglobulin G (IgG) (FcγR) represents a good example of how controlling the simultaneous triggering of activatory and/or inhibitory receptors results in a balanced immune response. FcγRs play a crucial role in linking the antibody‐mediated recognition of pathogens, allergens or auto‐antigens to the cellular arm of the immune response. In this review, we detail how dysfunction in FcγR pathways is linked to the development of the autoimmune disease, systemic lupus erythematosus.     

Role of the Fcγ receptor IIA polymorphism in the antiphospholipid syndrome: An international meta‐analysis

Objective

To assess the impact of the FcγRIIA‐R/H131 polymorphism on the risk for antiphospholipid syndrome (APS), both primary and secondary to systemic lupus erythematosus (SLE).

Methods

This international meta‐analysis combined data from 9 research teams. FcγRIIA‐R/H131 genotypes were determined in 481 APS cases (206 with primary APS), 1,420 SLE controls, and 1,655 disease‐free controls. Data were combined using fixed‐effects and random‐effects models.

Results

Compared with disease‐free controls, the RR genotype was enriched in the entire group of APS cases (odds ratio [OR] 1.65, 95% confidence interval [95% CI] 1.28–2.14); this was driven mostly by patients with secondary APS (OR 1.95, 95% CI 1.45–2.63). The excess of RR homozygotes but not heterozygotes among APS patients suggested a recessive mode of inheritance, rather than the additive model seen for SLE susceptibility, where RR conferred greatest risk, and RH intermediate risk, for SLE. This probably reflected the additional influence of another opposing genetic effect of HH homozygosity on APS predisposition (OR 0.72 for RH versus HH, 95% CI 0.55–0.96). Among SLE patients, those with APS were more frequently HH homozygotes than heterozygotes (OR 0.56 for RH versus HH, 95% CI 0.39–0.81). HH homozygosity also tended to predominate in primary APS compared with secondary APS (OR 0.50 for RR versus HH, 95% CI 0.25–0.99 by fixed‐effects model). There was no significant between‐study heterogeneity for any of these effects.

Conclusion

The FcγRIIA‐R/H131 polymorphism is an important determinant of predisposition to APS, with different influences on SLE and APS susceptibility per se.

     

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.

     

Cigarette smoking and the risk of systemic lupus erythematosus: A meta‐analysis

Objective

Existing studies present conflicting evidence for the role of cigarette smoking as a risk factor in the development of systemic lupus erythematosus (SLE). We performed an extensive search of the medical literature for all studies examining this relationship, and performed a meta‐analysis to arrive at a more precise estimate of effect.

Methods

We performed a computerized literature search for all studies (in all languages), using Medline and EMBASE (1966 to present) and the Cochrane Collaboration database, and completed hand searches of relevant bibliographies and abstracts of conference proceedings. Several investigators systematically extracted data from the relevant studies. Unpublished data were obtained from the author of one abstract. Studies were examined in aggregate for heterogeneity and publication bias. The relationships of current smoking and past smoking (prior to the onset of SLE) to development of SLE were analyzed separately.

Results

Fifty‐two studies were identified and chosen for detailed review. Of these, 9 (7 case–control and 2 cohort studies) were appropriate for inclusion in our meta‐analyses. For current smokers compared with nonsmokers, the odds ratio (OR) for development of SLE was significantly elevated (OR 1.50, 95% confidence interval [95% CI] 1.09–2.08). Former smokers, compared with nonsmokers, did not demonstrate an increased risk of SLE (OR 0.98, 95% CI 0.75–1.27). Several subgroups were also analyzed.

Conclusion

Our meta‐analysis of the 7 existing case–control and 2 cohort studies revealed a small but statistically significant association between current smoking and development of SLE. However, no association between past smoking and development of SLE was observed.

     

Association of a transmembrane polymorphism of Fcγ receptor IIb (FCGR2B) with systemic lupus erythematosus in Taiwanese patients

Objective

To investigate the possible association of the Fcγ receptor IIb (FcγRIIb) Ile/Thr187 transmembrane domain polymorphism, which significantly affects receptor signaling, with susceptibility to systemic lupus erythematosus (SLE) in Taiwanese patients.

Methods

We used matrix‐assisted laser desorption ionization−time‐of‐flight mass spectrometry to genotype 351 Taiwanese SLE patients and 372 age‐ and sex‐matched healthy individuals from the same geographic area. Allele frequencies and genotype distributions were compared between the patients and controls, both as an aggregate and as stratified by sex, autoantibody profile, and clinical parameters. A combined analysis was conducted to assess the FCGR2B Thr187 allele as a common risk factor in different ethnic populations.

Results

The minor Thr187 allele was significantly associated with SLE in Taiwanese subjects (P = 0.017, odds ratio [OR] 1.989 [95% confidence interval (95% CI) 1.119–3.553]). Interestingly, male SLE patients showed enrichment of the Thr/Thr187 genotype (24%; 7 of 29) as compared with female SLE patients (10%; 32 of 322) (P = 0.043, OR 2.884 [95% CI 1.028–7.839]). Additionally, SLE patients with Thr/Thr187 and Ile/Thr187 genotypes were more likely to have pleural effusions (P = 0.038, OR 1.874 [95% CI 1.033–3.411]) and anti‐SSA/Ro antibody production (P = 0.046, OR 2.221 [95% CI 1.013–4.897]). Combined analysis of 4 groups of Asian patients strongly supported the association of the FCGR2B Thr187 allele with the lupus phenotype (P = 0.000159).

Conclusion

The FcγRIIb transmembrane polymorphism is a strong disease susceptibility candidate in epistasis with other genetic effects in Taiwanese and other Asian populations. It may also play a more prominent role in male patients with SLE.