Lupus gene 'protects against malaria'
11 August 2010
Researchers from the Cambridge Institute for Medical Research and colleagues found that people with two copies of a particular gene variant are more susceptible to developing lupus, but that the same variant also confers increased protection against the malaria parasite.
Systemic lupus erythematosus (SLE or lupus) is an autoimmune disease caused by a faulty immune system that attacks the body, leading to inflammation and tissue damage, often in the skin, joints and kidneys. It arises most frequently in black and Asian women.
The study looked at a variant of the gene FCGR2B, which has previously been linked to lupus in Asians and is commonly found in those from South-east Asia or sub-Saharan Africa. The gene produces a receptor that acts as a 'brake' on some functions of the immune system. The lupus-associated variant does not function normally, resulting in 'brake failure' and a hyperactive immune system.
"We wanted to find an explanation for why this genetic variant was more common in South-east Asians and sub-Saharan Africans than in Europeans," says lead researcher Professor Ken Smith from the Cambridge Institute. "We thought that this variant, as well as putting people at increased risk of lupus, might also decrease the risk of malaria - which might explain why it is more common in those originating from malaria-endemic areas."
The researchers compared the genes of 326 British lupus patients with those of 1296 normal controls. They also looked at 920 lupus patients and 1026 controls from Hong Kong. The analysis confirmed a strong association with lupus susceptibility in both Asians and Caucasians who had two copies of the FCGR2B gene variant (we inherit two copies of any gene, one from our mother and one from our father).
Next, working with colleagues from the KEMRI-Wellcome Trust Research Programme, they compared the genes of 1359 children with severe Plasmodium falciparum malaria and 2492 controls from a malaria-endemic region of Kenya, in two cohorts. Looking again at FCGR2B, they found that those with two copies of the gene variant were almost 50 per cent less likely to contract severe malaria.
"We showed that if children [have two copies] for this gene variant their chances of getting severe malaria were just over half that of those who weren't homozygous," says Professor Smith. "This is quite significant. It's about the same protective effect as those with heterozygous thalassaemia."
Thalassaemia and sickle-cell disease also confer protection against malaria. The level of protection found from two copies of the lupus gene was comparable to people who had one copy of the thalassaemia gene but not as strong as those with the sickle-cell gene.
The mechanism through which this protection works is entirely different, however. Thalassaemia and sickle-cell disease affect the shape of red blood cells. Lacking the lupus-linked gene appears to make macrophages (white blood cells) better at 'eating' malaria parasites, according to the team's previous studies in human cells and in mice - mice lacking the FCGR2B receptor developed less severe malarial disease.
Image: A child sits in a mosquito net, Kenya. Credit: Thomas Omondi/Department for International Development on Flickr
Reference
Willcocks LC et al. A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus. Proc Natl Acad Sci USA 2010;107(17):7881-5.
