A polymorphism in the human gene FCGR2B is associated with susceptibility to systemic lupus erythematosus (SLE), but it is also associated with protection against malaria, according to a new study published in PNAS. The polymorphism was most common in people of Southeast Asian and African origin (i.e. populations from areas endemic for malaria), implying that its protective effects against malaria could provide a survival advantage and explain its prevalence in these populations despite the increased risk of SLE.
Systemic lupus erythematosus is a chronic and systemic autoimmune disorder whilst malaria is an infectious disease caused by Plasmodium parasites. These two disparate diseases are in fact linked by their association with the gene FCGR2B, which is involved in immune regulation and encodes the Fc gamma receptor IIb. A single nucleotide change in FCGR2B, termed rs1050501, codes for a threonine instead of isoleucine in the FCGR2B protein, which in turn leads to a non-functional Fc gamma receptor IIb (FcγRIIbT232) that has been shown to be important for resistance against Plasmodium. Furthermore, rs1050501 had already been associated with SLE and the frequency of this allele was found to vary between people of different ethnicities—it is more common in Southeast Asians or East Africans than Caucasians.
Lisa. C. Willcocks and colleagues analysed the genotypes of 819 people with SLE from Hong Kong compared with 1,026 ethnically matched controls, and 326 Caucasian patients with SLE compared with 1,296 controls in the “largest study of this FCGR2B SNP in SLE performed so far.” They found that SLE was strongly associated with FcγRIIbT232 in both ethnic groups. Next, the investigators genotyped rs1050501 in children from an area in Kenya endemic for malaria—they analysed control children as well as children who had suffered from either repeated episodes of mild malaria or a severe form of malaria. They found children homozygous for FcγRIIbT232 (the rs1050501 allele was present on each chromosome pair) were protected against severe malaria. In contrast, the same allele did not protect against bacterial infection.
Willcocks et al. state that “the high mortality from malaria has resulted in the strongest known force for evolutionary selection in the recent history of the human genome.” They argue that the protective effects of FcγRIIbT232 against malaria could explain why the mutant receptor is most common in Africans and Southeast Asians; the frequency of the rs1050501 allele, like sickle-cell disease and thalassemia, being related to malarial endemicity. “Malaria seems to have driven retention of a polymorphism predisposing to a polygenic autoimmune disease, and this may begin to explain the ethnic differences seen in frequency of that disease,” write the authors.
Willcocks, L., Carr, E., Niederer, H., Rayner, T., Williams, T., Yang, W., Scott, J., Urban, B., Peshu, N., Vyse, T., Lau, Y., Lyons, P., & Smith, K. (2010). A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0915133107