ClinVar Genomic variation as it relates to human health

In 193 Japanese patients with SLE (152700) and 303 healthy controls, Kyogoku et al. (2002) found that homozygosity for an ile232-to-thr (I232T) polymorphism in the transmembrane region of the FCGR2B gene was significantly increased in SLE patients compared with controls. In Japanese and Thai cohorts, Hitomi et al. (2004) found that significant association of the FCGR2B 232thr/thr with SLE was observed only with the CD72 (107272) *1/*1 genotype. They suggested that the presence of the CD72 *2 allele may decrease risk for SLE conferred by FCGR2B 232thr/thr, possibly by increasing levels of an alternatively spliced isoform of CD72. Floto et al. (2005) genotyped 1,296 healthy white volunteers for the I232T polymorphism, identifying 81.1% as homozygous for the wildtype receptor with 17.9% heterozygous and 1.0% homozygous for the polymorphism. Macrophages from homozygotes showed enhanced immune complex-triggered upregulation of surface MHC class I and class II and greater phagocytic capacity than cells from wildtype or heterozygous individuals. Peripheral B cells from homozygotes showed reduced FCGR2B-mediated inhibition of B cell receptor-triggered proliferation. Membrane separation studies in human monocytes revealed that although wildtype FCGR2B readily partitioned into the raft-enriched gradient fractions, FCGR2B-232T was excluded from them. Floto et al. (2005) concluded that FCGR2B-232T is unable to inhibit activating receptors because it is excluded from sphingolipid rafts, resulting in the unopposed proinflammatory signaling thought to promote SLE. Kono et al. (2005) examined the impact of the 695T-C SNP (I232T) on the functional properties of Fc-gamma-RIIB by expressing each allele product in a human B cell line lacking endogenous Fc-gamma-RIIB. Fc-gamma-RIIB with thr232 was found to be significantly less potent than wildtype ile232 in inhibiting B cell receptor (BCR)-mediated phosphatidylinositol-3,4,5-trisphosphate accumulation, AKT1 (164730) and PLCG2 (600220) activation, and calcium mobilization. Thr232-containing protein also displayed decreased levels of tyrosine phosphorylation and SH2-containing 5-prime-inositolphosphate phosphatase recruitment, compared with ile232 after IgG Fc-mediated coligation with BCR. Thr232 was less effectively distributed to detergent-insoluble lipid rafts than ile232, in accordance with the importance of the transmembrane amino acid residues in the association of membrane proteins with lipid rafts. Given the crucial roles of lipid rafts in integrating BCR signaling, Kono et al. (2005) suggested that decreased association of Fc-gamma-RIIB thr232 could contribute to its impaired inhibitory potential. Clatworthy et al. (2007) found an increased frequency of the I232T polymorphism in Asian and African populations, broadly corresponding to regions where malaria is endemic (see 611162). The SLE-associated I232T polymorphism was associated with enhanced phagocytosis of Plasmodium falciparum-infected human erythrocytes. Clatworthy et al. (2007) concluded that FCGR2B is important in controlling the immune response to malaria parasites and suggested that polymorphisms predisposing to SLE in Asians and Africans may be maintained because the variants reduce susceptibility to malaria. By comparing genotypes of patients with SLE from Hong Kong and the UK with those of ethnically matched controls, followed by metaanalysis using with other studies on southeast Asian and Caucasian SLE patients, Willcocks et al. (2010) found that homozygosity for T232 was strongly associated with SLE in both ethnic groups. When studies in Caucasians and southeast Asians were combined, T232 homozygosity was associated with SLE with an odds ratio of 1.73 (P = 8.0 x 10(-6)). Willcocks et al. (2010) noted that the T232 allele of the SNP is more common in southeast Asians and Africans, populations where malaria is endemic, than in Caucasians. Homozygosity for T232 was significantly associated with protection from severe malaria in Kenyan children (odds ratio = 0.56; P = 7.1 x 10(-5)), but no association was found with susceptibility to bacterial infection. Willcocks et al. (2010) proposed that malaria may have driven retention of a polymorphism predisposing to a polygenic autoimmune disease and thus may begin to explain the ethnic differences seen in the frequency of SLE. (less)

In 193 Japanese patients with SLE (152700) and 303 healthy controls, Kyogoku et al. (2002) found that homozygosity for an ile232-to-thr (I232T) polymorphism in the transmembrane region of the FCGR2B gene was significantly increased in SLE patients compared with controls. In Japanese and Thai cohorts, Hitomi et al. (2004) found that significant association of the FCGR2B 232thr/thr with SLE was observed only with the CD72 (107272) *1/*1 genotype. They suggested that the presence of the CD72 *2 allele may decrease risk for SLE conferred by FCGR2B 232thr/thr, possibly by increasing levels of an alternatively spliced isoform of CD72. Floto et al. (2005) genotyped 1,296 healthy white volunteers for the I232T polymorphism, identifying 81.1% as homozygous for the wildtype receptor with 17.9% heterozygous and 1.0% homozygous for the polymorphism. Macrophages from homozygotes showed enhanced immune complex-triggered upregulation of surface MHC class I and class II and greater phagocytic capacity than cells from wildtype or heterozygous individuals. Peripheral B cells from homozygotes showed reduced FCGR2B-mediated inhibition of B cell receptor-triggered proliferation. Membrane separation studies in human monocytes revealed that although wildtype FCGR2B readily partitioned into the raft-enriched gradient fractions, FCGR2B-232T was excluded from them. Floto et al. (2005) concluded that FCGR2B-232T is unable to inhibit activating receptors because it is excluded from sphingolipid rafts, resulting in the unopposed proinflammatory signaling thought to promote SLE. Kono et al. (2005) examined the impact of the 695T-C SNP (I232T) on the functional properties of Fc-gamma-RIIB by expressing each allele product in a human B cell line lacking endogenous Fc-gamma-RIIB. Fc-gamma-RIIB with thr232 was found to be significantly less potent than wildtype ile232 in inhibiting B cell receptor (BCR)-mediated phosphatidylinositol-3,4,5-trisphosphate accumulation, AKT1 (164730) and PLCG2 (600220) activation, and calcium mobilization. Thr232-containing protein also displayed decreased levels of tyrosine phosphorylation and SH2-containing 5-prime-inositolphosphate phosphatase recruitment, compared with ile232 after IgG Fc-mediated coligation with BCR. Thr232 was less effectively distributed to detergent-insoluble lipid rafts than ile232, in accordance with the importance of the transmembrane amino acid residues in the association of membrane proteins with lipid rafts. Given the crucial roles of lipid rafts in integrating BCR signaling, Kono et al. (2005) suggested that decreased association of Fc-gamma-RIIB thr232 could contribute to its impaired inhibitory potential. Clatworthy et al. (2007) found an increased frequency of the I232T polymorphism in Asian and African populations, broadly corresponding to regions where malaria is endemic (see 611162). The SLE-associated I232T polymorphism was associated with enhanced phagocytosis of Plasmodium falciparum-infected human erythrocytes. Clatworthy et al. (2007) concluded that FCGR2B is important in controlling the immune response to malaria parasites and suggested that polymorphisms predisposing to SLE in Asians and Africans may be maintained because the variants reduce susceptibility to malaria. By comparing genotypes of patients with SLE from Hong Kong and the UK with those of ethnically matched controls, followed by metaanalysis using with other studies on southeast Asian and Caucasian SLE patients, Willcocks et al. (2010) found that homozygosity for T232 was strongly associated with SLE in both ethnic groups. When studies in Caucasians and southeast Asians were combined, T232 homozygosity was associated with SLE with an odds ratio of 1.73 (P = 8.0 x 10(-6)). Willcocks et al. (2010) noted that the T232 allele of the SNP is more common in southeast Asians and Africans, populations where malaria is endemic, than in Caucasians. Homozygosity for T232 was significantly associated with protection from severe malaria in Kenyan children (odds ratio = 0.56; P = 7.1 x 10(-5)), but no association was found with susceptibility to bacterial infection. Willcocks et al. (2010) proposed that malaria may have driven retention of a polymorphism predisposing to a polygenic autoimmune disease and thus may begin to explain the ethnic differences seen in the frequency of SLE. (less)