Research from the United Kingdom indicates that a single nucleotide polymorphism (SNP) in the TNFRSF1A gene encoding the receptor for tumor necrosis factor (TNF) 1 is associated with multiple sclerosis (MS) but not rheumatoid arthritis (RA) or other autoimmune conditions.1 The SNP directs expression of a novel, soluble form of TNFR1 that can block TNF function.
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“The discrepancy in the efficacy of TNF-blocking drugs between MS and other autoimmune conditions, including RA, has remained a puzzle for over 10 years,” says Calliope A. Dendrou, PhD, a postdoctoral researcher in the Fugger laboratory of Weatherall Institute of Molecular Medicine at the University of Oxford. “Our work demonstrates that unlike other conditions, TNF blocking is a generic MS risk factor. Thus, a prior knowledge of the MS association of rs1800693 and of the functional effects it confers could have helped to predict the poor outcome of TNF blocking drugs in MS.”
rs18000693 Appears to be Culprit
MS-related genome-wide association reports have shown that rs18000693 is the most associated SNP in the region (odds ratio for risk allele=1.12, (1.11–1.14); P = 4.1 x 10-14). Statistical imputation found no other variant that could better explain this MS association within the region.
Dr. Dendrou and colleagues next looked at individuals carrying the MS risk allele at this SNP, finding significant increases in splicing out of exon 6 from TNFR1 transcripts. Furthermore, they also found that this novel splice variant translated into protein in primary human cells.
The researchers functionally characterized the risk-associated protein (Δ6-TNFR1) encoded by this splice variant. Lastly, they demonstrated the soluble Δ6-TNFR1 is capable of binding and neutralizing TNF.
“Our main finding is that an MS genetic risk variant located in the TNFRSF1A gene directs the production of a soluble isoform of TNFR1 that can bind to and block TNF,” says Dr. Dendrou. “This risk effect mirrors the clinical experience with TNF blockers, whereby these drugs, whose properties are analogous (although greater in magnitude) to those of Δ6-TNFR1, have been found to promote or exacerbate the disease.”
Given that the majority of MS-associated variants have only modest effects on disease risk, the clinical value of finding functional consequences of any genetic change has been a topic of debate. The group’s work shows follow-up investigations in this area can be medically informative.
“The analysis of disease-associated genetic regions provides a unique opportunity to revolutionize our understanding of the diseases such as RA and MS using genetic insights alongside functional studies so as to achieve better healthcare for patients,” she notes. “Our proof-of-principle study shows that the functional follow-up of common disease-associated genetic variants—despite their typically small individual effects on disease risk—can be clinically meaningful and will therefore constitute an active line of investigation in the autoimmune disease field that may change our understanding of these conditions, and thus the way we treat them.”