We show that a SNP in human FCGR2B that abrogates receptor function is strongly associated with susceptibility to SLE in both Caucasians and Southeast Asians.
FcγRIIb-I232T is a hypofunctional polymorphism associated with lupus susceptibility in humans, an autoimmune disease linked to diminished deletion of autoreactive B cells.
Given that the murine lupus susceptibility locus Nba2 includes the IFN-regulated genes Ifi202 (encoding for the p202 protein), Aim2 (encoding for the Aim2 protein), and Fcgr2b (encoding for the FcγRIIB receptor), we investigated whether the IRF5/Blimp-1 axis could regulate the expression of these genes.
Thus CN of FCGR3B, which controls IC responses and uptake by neutrophils, and variations in FCGR2B, which controls factors such as antibody production and macrophage activation, are important in SLE pathogenesis.
We have identified a polymorphism FCGR2B c.695T>C that results in the non-conservative replacement of 232Ile at the transmembrane helix to Thr and demonstrated the association of the polymorphism with susceptibility to systemic lupus erythematosus (SLE) in Asians.
Interestingly, recent studies involving the generation of Nba2 subcongenic mouse lines and generation of mice deficient for the Fcgr2b or Aim2 gene within the interval have provided evidence that epistatic interactions among the Nba2 genes contribute to increased lupus susceptibility.
Combined analysis of 4 groups of Asian patients strongly supported the association of the FCGR2B Thr187 allele with the lupus phenotype (P = 0.000159).
Our study demonstrated an association of FcγRIIB polymorphisms with SLE and lupus nephritis and a lack of association of FcγRIIA polymorphisms with SLE in the Egyptian patients.
We previously demonstrated significant association of the polymorphism of the CD72 gene with susceptibility to human systemic lupus erythematosus (SLE) in individuals carrying a SLE-susceptible FCGR2B genotype (FCGR2B-232Thr/Thr).
Indeed, recent epidemiological studies revealed that a non-synonymous single nucleotide polymorphism (rs1050501) within the TM domain of FcγRIIB, responsible for the I232T substitution, is associated with the susceptibility to systemic lupus erythematosus (SLE).
To examine the possibility that another susceptibility gene of primary significance exists within the FcgammaR region, we screened for polymorphisms of the human FCGR2B gene, and examined whether these polymorphisms are associated with SLE.
Using the two Asian cohorts, significant association of FCGR2B-232Thr/Thr with SLE was observed only in the presence of CD72-*1/*1 genotype (OR 4.63, 95% CI 1.47-14.6, P=0.009 versus FCGR2B-232Ile/Ile plus CD72-*2/*2).
We have identified a polymorphism FCGR2B c.695T>C that results in the non-conservative replacement of 232Ile at the transmembrane helix to Thr and demonstrated the association of the polymorphism with susceptibility to systemic lupus erythematosus (SLE) in Asians.
In FCGR2B encoding an inhibitory receptor expressed in B cells, monocytes and dendritic cells, a polymorphism within the transmembrane region, Ile232Thr, was identified and found to be associated with susceptibility to SLE in three Asian populations.
This mechanism could be responsible for the decreased expression of FcgammaRIIb associated with the -343 C/C homozygous FCGR2B genotype in lupus patients.
Recently, among other mutations, rare null-alleles for the deoxyribonuclease 1 like 3 (<i>DNASE1L3</i>) and the Fc gamma receptor IIB (<i>FCGR2B</i>) have been described in SLE patients and genetic mouse models.