TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis

Genome-wide association studies in combination with functional analyses identify a genetic variant that explains why anti-tumour necrosis factor therapy, used in several autoimmune diseases, exacerbates multiple sclerosis. Genetic variation in multiple sclerosis Recent genome-wide association studies (GWAS) have indicated an association between multiple sclerosis and a single-nucleotide polymorphism in the TNFRSF1A gene that encodes tumour necrosis factor (TNF) receptor 1 (TNFR1). TNF has previously been implicated in autoimmunity and TNF antagonists are effective treatments in several autoimmune diseases, but not in multiple sclerosis. Interestingly, GWAS evidence shows no link between TNFRSF1A and multiple sclerosis. This study compares GWAS results across different autoimmune conditions, as well as findings from functional and biophysical investigations, to show that multiple sclerosis-associated genetic risk at the TNFR1 locus results in the generation of a novel, endogenous TNF antagonist. This genetic-risk effect parallels the effects of anti-TNF therapy, which has been reported — in rare cases — to induce clinical onset of multiple sclerosis. Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS) 1 , it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance 2 . Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS) 3 , 4 , but not with other autoimmune conditions such as rheumatoid arthritis 5 , psoriasis 6 and Crohn’s disease 7 . By analysing MS GWAS 3 , 4 data in conjunction with the 1000 Genomes Project data 8 we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS 9 , 10 , 11 , but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the cli