Association analysis of functional variants of the FcgRIIa and FcgRIIIa genes with type 1 diabetes, celiac disease and rheumatoid arthritis

Abstract

FcgRIIa and FcgRIIIa are potent modulators of the immune system which bind (auto)antibodies and activate immune cells. The FcgRIIa*A519G and FcgRIIIa*A559C functional variants have been associated with several immune-related diseases. We studied FcgRIIa*A519G and FcgRIIIa*A559C SNPs in type 1 diabetes (T1D), celiac disease (CD) and rheumatoid arthritis (RA) patients and controls and included a meta-analysis of all recent studies of FcgRIIIa*A559C and RA. Our cohorts comprised 350 T1D, 519 CD, 639 RA patients and 1359 controls, who were genotyped for FcgRIIa*A519G and FcgRIIIa*A559C variants. Regression and expectation maximization (EM) algorithm-based haplotype analyses were used for the data analysis. We found significant differences in genotype frequencies of FcgRIIa between controls and patients with T1D (P = 0.04), CD (P = 0.000005) and RA (P = 0.04). The FcgRIIa*519GG genotype showed an increased risk for both T1D [odds ratio (OR) = 1.51; 95% confidence interval (95% CI) 1.08-2.12; P = 0.015] and CD (OR = 1.81; 95% CI 1.35-2.37; P = 0.000004), but not for RA. There was no difference in the frequency of FcgRIIIa*A559C genotypes or allelotypes between controls with T1D, CD and RA. We found that FcgRIIa and FcgRIIIa haplotype frequencies differed significantly between controls and patients with T1D (P = 0.05) and with CD (P = 0.00038) but not with RA. Our meta-analysis showed a significant 1.37(95% CI 1.14-1.66)-fold increased risk of RA for the FcgRIIIa*559CC (158VV) genotype (P = 0.001). This is the first report that the FcgRIIa*519GG genotype predisposes to T1D and CD. We confirmed that the FcgRIIIa*559CC genotype is associated with RA. If replicated, our findings would suggest FcgRIIa*519G as a common risk factor for auto-immune diseases. This may have clinical implications with regard to efficacy or safety of antibody-based immuno-modulator therapies.

Association study of IL2/IL21 and FcgRIIa: significant association with the IL2/IL21 region in Scandinavian coeliac disease families

“…2 and one by Alizadeh et al,7 reported association between CD and KIAA1109/Tenr/IL2/ IL21 and FcgRIIa, respectively. Both of these studies were based on a case-control approach, and one purpose of our study was to replicate the most associated SNPs from these publications in a family sample using TDT to avoid the possibility of a false positive finding due to population stratification.…”

“…7 FcgRIIa is a low affinity activating Fcg receptor that binds immune complexes. Ligation of this Fc receptor leads to phagocytosis, dendritic cell maturation, increased stimulation of T cells and enhanced secretion of inflammatory cytokines.…”

“…7 The unequivocal identification of IL2, IL21 and FcgRIIa as susceptibility genes in CD will have great implications for the understanding of the pathogenesis of this disease. The understanding of the molecular mechanisms of CD has made substantial advances in recent years, 10 and disease associated genes and gene variants can be readily tested in relevant disease models involving glutenreactive T-cell clones and disease specific anti-gluten and anti-transglutaminase antibodies.…”

Copy number variation in the human genome and its implication in autoimmunity

“…This study also revealed that FCRGR3A varies in copy numbers, but compared with FCGR3B at a much lower frequency. The FCRGR3A gene was found to be associated with rheumatoid arthritis (RA) [31,32]. In particular, a strong association for RA susceptibility was found for the FCGR3A-FCGR3B NA2 haplotype [33].…”

Antigen-Presenting Cells and their Fcγ and Toll-Like Receptors: Leading Suspects in Autoimmunity

“…More recently also non-HLA genes have been linked to RA susceptibility and disease severity. Variants of the activating Fc gamma receptors Fc RIIIa and Fc RIIIb have been associated with RA susceptibility in Europeans, but not in Asians [69,70]. The Fc RIIIa variant is less effective in IC binding, implicating impaired clearance of ICs might play a role in the pathogenesis of RA, similar to SLE [71].…”