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Researchers identify gene variant that confers risk for multiple sclerosis and lupus

An international team of researchers, including scientists from NIA’s Intramural Research Program, have identified an important new genetic variant that increases risk for two autoimmune diseases: multiple sclerosis (MS) and systemic lupus erythematosus (lupus). The results were reported in the New England Journal of Medicine on April 27, 2017. The study was led by Dr. Francesco Cucca, director of the Institute of Genetic and Biomedical Research of the Italian National Research Council.

MS and lupus are autoimmune diseases caused when a person’s immune system attacks their own normal tissues: the myelin coating of nerves is targeted in MS, while the skin, kidneys, and other organs are affected in lupus. While scientists have long suspected a genetic predisposition to risk for autoimmune disorders, this study is the first to identify a specific genetic variation that is associated with the two diseases.

The researchers first performed a full genetic sequencing of more than 3,000 people with MS or lupus and a similar number of unaffected individuals in the Mediterranean island of Sardinia. Extensive characterization of the immune system was also performed on this group. The process was repeated in almost 22,000 case and control individuals from mainland Italy, Spain, the United Kingdom, and Sweden, reproducing the original results.

The research team found a correlation between a particular variant of the TNFSF13B gene and the development of the autoimmune diseases. The TNFSF13B gene produces the protein BAFF, the B-cell activating factor, which is needed for survival and growth of B cells, the cells in the body’s the immune system that protect against infections. The researchers found that while normal BAFF production is strongly suppressed by cellular factors, BAFF production driven by the genetic variant is not affected by these same factors. The resulting increase in BAFF leads to correspondingly higher numbers of B cells, elevated antibody production, and increased risk of autoimmunity.

The researchers note that the findings validate BAFF as a possible drug target for MS, lupus, and possibly other autoimmune disorders. The identification of this variant at the population, cellular, and molecular levels also illustrates a new association of a TNFSF13B variant with autoimmunity. This discovery may help to optimize individual therapy for these diseases and aid in the development of new therapies.

Reference: Overexpression of the cytokine BAFF and autoimmunity risk. Steri, M., et al. The New England Journal of Medicine, April 27, 2017.