Research: MS Genes, Why MouseDoc is not in the money

Gregory AP et al. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature (2012) doi:10.1038/nature11307Received 29 November 2011 Accepted 10 June 2012 Published online 08 July 2012

Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS) 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. Here we have investigated a single nucleotide polymorphism (SNP) in theTNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data 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, 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.



Many years ago MouseDoc and a Doc from Oxford ( who was from London at that time) filed a patent on the use of anti-TNF for the treatment of MS. The doc from Oxford was the guy that got me talking with a young Prof G just after he came from South Africa)

This Doc from Oxford (then London) had also filed a patent on the use of anti-Tumour Necrosis Factor (A protein that causes cancers to die) for the treatment of Rheumatoid Arthritis, which is an autoimmune disease of the joints.

I would say this was the first rationally-designed drug that moved from the bench to the person with autoimmune disease, under the control of the Doc from Oxford, that had a real impact on Arthritis.  

Anti-TNF treatments went on to become blockbuster drugs for rheumatoid arthritis and Crohns Disease, with a market of 22 billion dollars in 2009. The Doc from Oxford (then London) has done alright out of this, but in contrast to the patent for Arthritis written on cash, the patent for MS was sadly written on toilet paper. 

This is because when anti-TNF was tried in MS, there was an apparent worsening of disease. The use of the drug for MS was shelved forever and no inventor fee for me.

Twenty or so years on some other Docs from Oxford think they have found out a potential reason for this. When they looked for genes that associate with MS susceptibility they found something in one of the TNF receptor genes. Tumor necrosis factor receptor (TNFR), or death receptor, is a trimeric cytokine receptor that binds tumor necrosis factors (TNF). The receptor cooperates with an adaptor protein (such as TRADD, TRAF, RIP), which is important in determining the outcome of the response (e.g. apoptosis = cell suicide, inflammation).Because "TNF" is often used to describe TNF alpha, "TNFR" is often used to describe the receptors that bind to TNF alpha - namely,CD120


It seems that the genetic variant associated with MS codes for a shortened version of the TNF receptor that lacks the molecules that would anchor it in the membrane. It is thought that this can be secreted and so mops up TNF floating around the blood and brain. 

Whilst the risk of developing MS if you have this variant is not a lot greater than if you do not have the gene variant, it is suggested that the blockade of TNF by anti-TNF antibody does the same thing but has a greater impact and this is why it triggers MS.

In contrast this variant is not associated with the development of rheumatoid arthritis  or Crohns disease where anti-TNF inhibits disease. This suggests that if one were to track down and see which people developed worse MS after anti-TNF treatment they would all have this variant?   However it appears that only 30% of MS have this variant, which would suggest that 70% of MSers should actually benefit from treatment compared to placebo, if this idea is correct. 

In previous trials 15/43 (35%) had a relapse compared to 28/40 (70%) in TNF treated MSers within 6 months of treatment (P=0.003), although there was no evidence of increased MRI? Therewas no evidence that a subset of Msers got worse whilst some got better.


I am not sure whether anti-TNF worsening MS was because there is soluble anti-TNF R1 variant, but it is plausible. However, it needs to be remembered that TNF and TNF receptors are not just on immune cells, they occur on astrocytes, oligodendrocytes etc. Following Alemtuzumab treatment in the absence of steroids, which stops the response, you get a cytokine storm including TNF release. This reactivates your old MS lesions so it suggests that can be involved in neural signalling. In addition TNFR1 is involved in killing of cells so with the truncated variant you may not get killing of cells so perhaps in the blood it means that your immune cells do not get regulated and killed and so you get more immune responsiveness, but in the CNS it could mean that less damage to oligodendrocytes, which can be killed via signalling through TNFR1. The short variant would not have this signalling function. 

However one thing it tells us is that you can not assume that a drug that works in arthritis is going to work in MS!


This study suggests that by understanding and detecting the genetic variants that are associated with MS and treatment response, we may be able to predict how one is going to respond to drugs. This is known as pharmacogenomics and will no doubt become of increasing importance in the future as we aim to maximise treatment effects, whilst limiting adverse effects. 

It  took about ten years and millions and millions of dollars to sequence the first human genome, now you can do it just a few days for a couple of thousand dollars. So if you think about the costs of the drugs then such a test could be well worth it, if you could know if the drug would not work etc.

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