Scientists have identified a gene variant which explains why patients with multiple sclerosis do not respond to a class of drugs used successfully in other autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease.
The study, published in Nature, explains why a clinical trial completed ten years ago found that anti-tumour necrosis factor drugs (anti-TNFs) actually make MS symptoms worse.
Researchers from Oxford University, along with German, Danish and US colleagues, illustrated how some changes in the DNA code could affect how patients respond to treatment.
The team used a battery of genetic, molecular, cell biology and biophysical techniques to show that the TNFRSF1A gene variant results in the production of an altered, shortened version of the TNFR1 protein encoded by the gene.
The long version of the TNFR1 protein normally sits at the surface of cells and binds TNF, but the shortened form lacks an anchor to keep it at the cell surface and is instead released outside of the cell.
The shortened version then 'mops up' TNF, preventing it from triggering signals - essentially the same action as TNF-blocking drugs.
Adam Gregory of the Nuffield Department of Clinical Neurosciences at Oxford University and joint author of the study said: "Now we know that the functional effect of the TNFRSF1A gene variant mirrors that of TNF blocking drugs and this promotes MS risk."
Professor Lars Fugger, who led the research, said the results are a proof of concept that understanding the biological details of how gene variants are associated with a disease can direct which patients should or should not receive specific drugs.
"Whilst the TNFRSF1A gene variant is linked to a modest risk of developing MS, the drug that mimics the effect of the variant has a considerably greater impact. The effects of genetic variants influencing disease risk or resistance can be amplified by drugs. This has often been completely overlooked but will be critical for using genetic findings in a medical context."