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

Abstract

Objective. To investigate the possible association of the Fc␥ receptor IIb (Fc␥RIIb) 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 Fc␥RIIb exhibits several apparent inhibitory activities in modulating the immune system, but not all the inhibitory activities are dependent on its distinct ITIM. Coengagement of Fc␥RIIb and other receptors containing an immunoreceptor tyrosine-based activation motif (ITAM) leads to tyrosine phosphorylation of the ITIM by Lyn kinase, recruitment of SH2 domain-containing inositol phosphatase (SHIP), inhibition of ITAMtriggered calcium mobilization, and arrest of cellular proliferation (3). Inhibition of calcium mobilization requires the phosphatase activity of SHIP to hydrolyze phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ), and the

A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus

“…Although previous small studies have reported an association of FcγRIIb T232 with SLE in Asians (13)(14)(15)(16), no such association had been shown in two studies in Caucasians (17,18). We found this surprising, because the functional effect of the polymorphism in vitro is seen in B cells and monocyte-derived macrophages from Caucasian individuals (11).…”

“…A recessive model was used for two reasons. First, previous genetic studies had suggested that homozygosity for FcγRIIb T232 was associated with SLE (13,15). Second, the polymorphism disables the receptor (11,12), and thus, functional deficiency of the receptor in minor allele homozygotes would be consistent with a recessive effect.…”

“…We found this surprising, because the functional effect of the polymorphism in vitro is seen in B cells and monocyte-derived macrophages from Caucasian individuals (11). The minor allele frequency (MAF) of rs1050501 is subject to considerable ethnic variation, being lower in Caucasians (0.10) (19) than East Africans (0.25) (19) or Southeast Asians (0.22-0.25) (13)(14)(15)(16). This low allele frequency meant that previous studies in Caucasians were underpowered to detect the odds ratio (OR) observed in Southeast Asians (power < 21%).…”

<i>FcγRIIB </i>Gene Polymorphisms Are Associated with Disease Risk and Clinical Manifestations of Systemic Lupus Erythematosus in Koreans

“…Several genetic association studies of FCGRIIB have been reported in different ethnic populations with SLE, including Japanese (Kyogoku et al 2002), Thais (Siriboonrit et al 2003), Chinese (Chu et al 2004;Chen et al 2006;Pan et al 2008), and Swedish (Magnusson et al 2004).…”

“…Humans have 5 lowaffinity FcγRs, termed FCGRs, encoded by FCGRIIA, FCGRIIB, FCGRIIC, FCGRIIIA, and FCGRIIIB. FCGRIIB is the only inhibitory FcγR, which contains an immunoreceptor tyrosine-based inhibitory motif (Smith and Clatworthy 2010) and is possible candidate gene for SLE (Kyogoku et al 2002;Magnusson et al 2004;Chen et al 2006). Serum concentrations of C-reactive protein (CRP) in humans are indicative of inflammation and pathological progression of an infection.…”