Increased Risk of Autoimmune Diseases Linked to Malaria-resisting Gene Variation
A variation in a gene that likely promoted resistance to malaria in Sardinia may have increased the risk of people there developing autoimmune diseases such as multiple sclerosis (MS) and systemic lupus erythematosus (SLE).
The study, “Overexpression of the Cytokine BAFF and Autoimmunity Risk,” was published in The New England Journal of Medicine.
Autoimmune diseases are caused by still largely unknown environmental factors that affect some people more than others. This is because we all carry genome differences, so some of us are genetically more susceptible to the factors than others.
Researchers have done what are known as genome-wide association studies of autoimmune diseases to try to detect which genome variations are associated with particular diseases. They identified only a few genes that cause diseases, however. And they were unable to learn how most of the genes cause the diseases.
So an American team tried a different approach to identifying the mechanisms that underlie autoimmune diseases. Understanding those mechanisms could lead to therapies that target those pathways, they felt.
The new approach was searching for DNA variations that increase the risk of a person developing an autoimmune disease and looking at levels of immune system components, including different kinds of immune cells and proteins known as cytokines.
They did this by performing a genome-wide association study among residents of Sardinia, an Italian island where there are high rates of MS and lupus.
Researchers linked a variation in the TNFSF13B gene to both diseases. The gene encodes a cytokine called B-cell activating factor (BAFF).
They concluded that the higher risk of MS and SLE associated with this variation is likely due to increased levels of BAFF in the blood of Sardinian residents. The higher BAFF levels lead to a hyperactive immune system, which increases the risk of developing an autoimmune disease, they decided.
The results support BAFF as a target for treating MS and SLE. Another important implication for research is that patients with high levels of BAFF may be unable to respond well to autoimmune therapies, the team said.
They also wondered why a variation that increases the risk of autoimmune diseases evolved in Sardinia.
One hypothesis was that it may have provided resistance to malaria. “BAFF-var may have been positively selected in Sardinia by providing resistance to Plasmodium falciparum or P. vivax malaria, both of which were strikingly prevalent in Sardinia until their eradication in the 1950s,” the team wrote.
“Overall, the evolutionary scenario we propose is that BAFF-var was selected as an adaptive response to malaria infection, resulting in an increased present-day risk of autoimmunity,” the researchers concluded.