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

Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease more prevalent in people of African and Asian origin than Caucasian origin. FcγRIIb is an inhibitory Fc receptor with a critical role in immune regulation. Mouse data suggest that FcγRIIb deficiency increases susceptibility to autoimmune disease but protects against infection. 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. The minor allele of this SNP is more common in Southeast Asians and Africans, populations from areas where malaria is endemic, than in Caucasians. We show that homozygosity for the minor allele is associated with substantial protection against severe malaria in an East African population (odds ratio = 0.56; P = 7

Genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice

“…A single nucleotide polymorphism in the gene encoding the human FcγRIIB that abrogates receptor function is strongly associated with susceptibility to SLE in both Caucasians and Southeast Asians (13). Willcocks et al (12) recently reported that the minor allele of this polymorphism is more common in Southeast Asians and Africans than in Caucasians and that homozygosity for the minor allele is associated with substantial protection from severe malaria in children in Kenya (12), although this study was not powered to detect associations with a specific type of severe malaria, for example cerebral malaria versus severe malaria anemia. Consistent with the observation by Willcocks et al, it was shown earlier that macrophages from individuals homozygous for this polymorphism efficiently engulfed Pf trophozoites (11).…”

“…Indeed, FcγRIIB deficiency in mice has been shown to reduce the severity of nonfatal Plasmodium chabaudi infections that correlated with increased levels of the proinflammatory cytokine TNF-α and with increased antibody levels (11). Willcocks et al (12) recently provided evidence that a loss-of-function polymorphism in FcγRIIB is associated with protection from severe malaria in African children. In addition to the FcγRIIB deficiency, FcγRIIB −/− .yaa mice have the Y chromosome-linked genetic modifier Yaa, a duplication in the gene that encodes Toll-like receptor 7 (TLR7) (14), a member of one family of the innate immune system's pathogen-associated molecular pattern recognition receptors.…”

“…We analyzed FcγRIIB −/− .yaa mice that are deficient in FcγRIIB, an inhibitory receptor that is central to the control of humoral immune responses (8). FcγRIIB was of particular interest because a human allele that encodes a polymorphism in the transmembrane domain in FcγRIIB that results in a loss of function (9, 10) is significantly more common in Africans (11,12) and in African Americans (9) than in Europeans and is associated with SLE in Asia (13). Indeed, FcγRIIB deficiency in mice has been shown to reduce the severity of nonfatal Plasmodium chabaudi infections that correlated with increased levels of the proinflammatory cytokine TNF-α and with increased antibody levels (11).…”

FcγRIIb inhibits immune complex-induced VEGF-A production and intranodal lymphangiogenesis

“…Elevated VEGF-A has been noted in patients with rheumatoid arthritis and SLE and correlates with disease activity (24,25). In humans, a nonsynonymous SNP in FCGR2B (rs1050501) (isoleucine to threonine at position 232) leads to receptor dysfunction and confers susceptibility to SLE (5,26). We hypothesized that rs1050501 would affect VEGF-A production in individuals with the SLE-associated FcγRIIB T232 receptor.…”

Prospecting for Precision: Promises for Personalized Medicine

“…It is interesting to note that rs1050501, a nonsynonymous SNP at position 161643798 in the genomic region encoding the transmembrane segment of FcγRIIb (Ile232Thr), is a strong risk factor for systemic lupus in multiple East Asian populations, but not in white populations 16,17 . It lies between rs1771568 and rs10917686 (see Table 2 1 , Kim and Bang) and might be involved in the proposed association of rs6697139 with therapeutic response.…”