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

Nature. 2012 Aug 23;488(7412):508-511. doi: 10.1038/nature11307.

Adam P Gregory ^# ¹, Calliope A Dendrou ^# ², Kathrine E Attfield ², Aiden Haghikia ² ³, Dionysia K Xifara ⁴, Falk Butter ⁵, Gereon Poschmann ⁶, Gurman Kaur ¹, Lydia Lambert ², Oliver A Leach ², Simone Prömel ², Divya Punwani ¹, James H Felce ¹, Simon J Davis ¹, Ralf Gold ³, Finn C Nielsen ⁷, Richard M Siegel ⁸, Matthias Mann ⁵, John I Bell ⁹, Gil McVean ⁴, Lars Fugger ¹ ² ¹⁰

Affiliations

1 MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
2 Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
3 Department of Neurology, St. Josef-Hospital Bochum, Ruhr-University Bochum, 44791 Bochum, Germany.
4 Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
5 Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, D-82152 Martinsried, Germany.
6 Molecular Proteomics Laboratory, Biologisch-Medizinisches Forschungszentrum, Heinrich-Heine Universität Düsseldorf, D-40225 Düsseldorf, Germany.
7 Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark.
8 Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH, 10 Center Drive, Bethesda, MD 20892-1930, USA.
9 Richard Doll Building, Roosevelt Drive, University of Oxford, Oxford OX3 7DG, UK.
10 Clinical Institute, Aarhus University Hospital, Skejby Sygehus, 8200 N Aarhus, Denmark.
# Contributed equally.

PMID: 22801493 DOI: 10.1038/nature11307

Abstract

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 the TNFRSF1A 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.

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