TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis.
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.
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Adam P
AP
Gregory
Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Calliope A
CA
Dendrou
Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Kathrine E
KE
Attfield
Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.|Department of Neurology, St. Josef-Hospital Bochum, Ruhr-University Bochum, 44791 Bochum, Germany.
Aiden
A
Haghikia
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
Dionysia K
DK
Xifara
Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, D-82152 Martinsried, Germany.
Falk
F
Butter
Molecular Proteomics Laboratory, Biologisch-Medizinisches Forschungszentrum, Heinrich-Heine Universität Düsseldorf, D-40225 Düsseldorf, Germany.
Gereon
G
Poschmann
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Gurman
G
Kaur
Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Lydia
L
Lambert
Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Oliver A
OA
Leach
Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Simone
S
Prömel
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Divya
D
Punwani
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
James H
JH
Felce
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Simon J
SJ
Davis
Department of Neurology, St. Josef-Hospital Bochum, Ruhr-University Bochum, 44791 Bochum, Germany.
Ralf
R
Gold
Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark.
Finn C
FC
Nielsen
Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH, 10 Center Drive, Bethesda, MD 20892-1930, USA.
Richard M
RM
Siegel
Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, D-82152 Martinsried, Germany.
Matthias
M
Mann
Richard Doll Building, Roosevelt Drive, University of Oxford, Oxford OX3 7DG, UK.
John I
JI
Bell
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
Gil
G
McVean
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.|Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.|Clinical Institute, Aarhus University Hospital, Skejby Sygehus, 8200 N Aarhus, Denmark.
Lars
L
Fugger
D000483:Alleles; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D023281:Genomics; D005838:Genotype; D006801:Humans; D009103:Multiple Sclerosis / Q000139:chemically induced* / Q000188:drug therapy / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006113:United Kingdom
D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human; D014409:Tumor Necrosis Factor-alpha