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

Abstract

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 play in disease. Moreover, the modest contribution these variants make to disease risk has raised questions regarding their medical relevance2. We have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes TNF 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 (RA)5, psoriasis6 and Crohn’s disease7. By analyzing MS GWAS3,4 data in conjunction with the 1000 Genomes Project data8 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 MS9-11, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.

Peripheral elevation of TNF-α leads to early synaptic abnormalities in the mouse somatosensory cortex in experimental autoimmune encephalomyelitis

“…A polymorphism of multiple sclerosis in the TNFRSF1A gene, encoding for TNFR1, has been shown to mimic TNF blockade and cause a more severe clinical outcome (61). Future studies are needed to investigate the reasons for differential responses to anti-TNF therapy among EAE, MS, and other neuroinflammatory diseases.…”

10 Years of GWAS Discovery: Biology, Function, and Translation

“…24 Transethnic studies have demonstrated substantial genetic overlap between ethnically remote populations; 106 109 The SNP leads to loss of the transmembrane domain of the receptor, and the risk SNP for MS (protective for AS) leads to increased serum soluble TNF receptor. 110 TNF inhibition, including by decoy TNF receptor therapies, is highly effective for AS and many other immune-mediated diseases, but its use can be complicated by de novo development of MS, and in MS itself, it can exacerbate disease. Although this is a retrospective example, it demonstrates the potential of using genetics to predict toxicities.…”

Genetics of complex diseases: knowing gene polymorphisms do matter

“…A GWAS screening revealed a SNP (rs 1800693), in the tumor necrosis factor receptor (TNFR) gene, that was associated with disease susceptibility. This genetic variation was responsible for a rare soluble form of TNFR that blocks circulating TNF 4 and has been suggested that TNF blockage could trigger MS. Curiously, anti-TNF drugs (such as infliximab) largely used for other inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn´s disease can also trigger multiple sclerosis indicating clearly that genome-based analysis unveiling SNPs are being associated with different complex diseases and their mechanisms of action can be copied using different types of immunobiologicals or drugs.…”