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

Abstract

Objective. Human low-affinity Fc␥ receptors (Fc␥R) constitute a clustered gene family located on chromosome 1q23, that consists of Fc␥RIIA, IIB, IIC, IIIA, and IIIB genes. Fc␥RIIB is unique in its ability to transmit inhibitory signals, and recent animal studies demonstrated a role for Fc␥RIIB deficiency in the development of autoimmunity. Genetic variants of Fc␥RIIA, 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 Fc␥R 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.Results of genome-wide linkage studies have suggested that the chromosomal region 1q23 is one of the strongest candidate regions for human systemic lupus erythematosus (SLE) (1,2), as well as its syntenic region in murine lupus (3). Three Fc␥ receptor type II

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

“…Our data support previous findings in 3 other Asian populations (29,32,33). However, the Fc␥RIIb Ile/ Thr187 polymorphism may require epistatic interaction with other genes to express the autoimmune phenotype.…”

“…There were significant differences in the genotype distribution between patients with and without pleural effusion ( 2 ϭ 6.59, P ϭ 0.037 by 3 ϫ 2 contingency Strong association of the FCGR2B Ile187Thr polymorphism and SLE in Asian populations. Several published association studies suggest that the FCGR2B minor allele, Thr187, is a risk factor for disease in Thai, Japanese, and Chinese populations, but not in American or Swedish Caucasian or in African American populations (28,29,(32)(33)(34). This differential result does not seem to reflect different population allele frequencies, since the frequencies of the Thr187 allele in these Asian 142 (51) 105 (38) 29 (11) 142 (51) 134 (49) 389 (70) 147 (56) 87 (33) 29 (11) 147 (56) 116 (44) 381 (72) 145 (28) Oral ulcer Positive (n ϭ 112) 59 (53) 42 (38) 11 (10) 0.752 59 (53) 53 (47) 0.853 160 (71) 64 (29) 1.000 Negative (n ϭ 239)…”

“…Several single-nucleotide polymorphisms (SNPs) have been identified in the promoter and coding regions of FCGR2B (26)(27)(28)(29). The SNP at position c.775TϾC (GenBank accession no.…”

A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities

“…These receptors are strong candidates for involvement in autoimmunity, as they are believed to play important roles in the pathogenesis of RA and other autoimmune diseases 18 . Region 1q23 represents a candidate locus for susceptibility to systemic lupus erythematosus (SLE), and variants in the classical FcγR II/III genes would partially account for disease susceptibility 6,19 25)). Although 1q21-23 is a strong candidate region for RA susceptible genes, as above mentioned, the association of classical FcγRs with disease susceptibility remains controvertial 26,27 .…”

B lymphocyte signaling pathways in systemic autoimmunity: Implications for pathogenesis and treatment

“…This region is syntenic to a region on mouse chromosome 1 in the vicinity of the Fc␥RIIB1 locus (33) and encodes a variety of immunologically relevant molecules, including Fc␥RIIb and Fc␥RIII, and poly(ADP-ribose) polymerase. More recently, the frequency of an SNP (695T/C) coding for a nonsynonymous Ile 232 /Thr substitution within the transmembrane domain of Fc␥RIIb was significantly increased in Japanese patients with SLE compared with healthy individuals (46). It is of further interest that another allele, called FCGR2B-187T, that mediates a higher level of CD19 dephosphorylation and a greater degree of inhibition of the Ca 2ϩ response when coengaged with the BCR than does FCGR2B-187I, is not associated with SLE in both African Americans and Caucasians (47).…”