No file available
To read the file of this research,
you can request a copy directly from the author.
New research to uncover cellular mechanisms driving risk for multiple sclerosis
Preprints and early-stage research may not have been peer reviewed yet.
Abstract
This paper provides a brief presentation on the genetics of multiple sclerosis susceptibility and on current work that uncovers the cellular effects, immunological and non-immunological, associated with genetic risk variants.
ResearchGate has not been able to resolve any citations for this publication.
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.
Substantial advances have elucidated some of the central mechanisms underlying the inflammation, demyelination, and neurodegeneration that occur in multiple sclerosis. Correspondingly, the clinical strategies available for the management of the disease have widened. This review focuses on the current knowledge of the pathogenesis of the inflammatory and neurodegenerative elements of the multiple sclerosis plaque.
Multiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor alpha chain (IL7R) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.
Multiple sclerosis (MS) is a common autoimmune disease that targets myelin in the central nervous system (CNS). Multiple genome-wide association studies (GWAS) over the past 10 years have uncovered more than 200 loci that independently contribute to disease pathogenesis. As with many other complex diseases, risk of developing MS is driven by multiple common variants whose biological effects are not immediately clear. Here, we present a historical perspective on the progress made in MS genetics and discuss current work geared towards creating a more complete model that accurately represents the genetic landscape of MS susceptibility. Such a model necessarily includes a better understanding of the individual contributions of each common variant to the cellular phenotypes, and interactions with other genes and with the environment. Future genetic studies in MS will likely focus on the role of rare variants and endophenotypes.
The transcription factor nuclear factor κB (NFκB) is a central regulator of inflammation, and genome-wide association studies in subjects with autoimmune disease have identified a number of variants within the NFκB signaling cascade. In addition, causal variant fine-mapping has demonstrated that autoimmune disease susceptibility variants for multiple sclerosis (MS) and ulcerative colitis are strongly enriched within binding sites for NFκB. We report that MS-associated variants proximal to NFκB1 and in an intron of TNFRSF1A (TNFR1) are associated with increased NFκB signaling after tumor necrosis factor-α (TNFα) stimulation. Both variants result in increased degradation of inhibitor of NFκB α (IκBα), a negative regulator of NFκB, and nuclear translocation of p65 NFκB. The variant proximal to NFκB1 controls signaling responses by altering the expression of NFκB itself, with the GG risk genotype expressing 20-fold more p50 NFκB and diminished expression of the negative regulators of the NFκB pathway: TNFα-induced protein 3 (TNFAIP3), B cell leukemia 3 (BCL3), and cellular inhibitor of apoptosis 1 (CIAP1). Finally, naïve CD4 T cells from patients with MS express enhanced activation of p65 NFκB. These results demonstrate that genetic variants associated with risk of developing MS alter NFκB signaling pathways, resulting in enhanced NFκB activation and greater responsiveness to inflammatory stimuli. As such, this suggests that rapid genetic screening for variants associated with NFκB signaling may identify individuals amenable to NFκB or cytokine blockade.
Copyright © 2015, American Association for the Advancement of Science.
We set out to characterize the clinical impact and functional consequences of rs1800693(G), the multiple sclerosis (MS) susceptibility allele found in the TNFRSF1A locus.
We analyzed prospectively collected data on patients with MS to assess the role of the TNFRSF1A locus on disease course and treatment response. Using archival serum samples and freshly isolated monocytes from patients with MS and healthy subjects, we evaluated the effects of rs1800693(G) and a second risk allele, R92Q, on immune function.
In 772 patients with MS, we see no evidence that rs1800693(G) strongly influences clinical or radiographic indices of disease course and treatment response; thus, rs1800693(G) appears to be primarily involved in the onset of MS. At the molecular level, this validated susceptibility allele generates an RNA isoform, TNFRSF1A Δ6, that lacks the transmembrane and cytoplasmic domains. While there was no measurable effect on serum levels of soluble TNFRSF1A, rs1800693(G) appears to alter the state of monocytes, which demonstrate a more robust transcriptional response of CXCL10 and other genes in response to tumor necrosis factor (TNF)-α. We also report that activation of the TNF-α pathway results in altered expression of 6 other MS susceptibility genes, including T-cell activation rho GTPase activating protein (TAGAP) and regulator of G-protein signaling 1 (RGS1), which are not previously known to be responsive to TNF-α.
The MS rs1800693(G) susceptibility allele affects the magnitude of monocyte responses to TNF-α stimulation, and the TNF pathway may be one network in which the effect of multiple MS genes becomes integrated.
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis
International Multiple Sclerosis Genetics Consortium. Analysis of immune-related loci identifies 48 new
susceptibility variants for multiple sclerosis. Nat Genet. 2013;45:1353-1360.
International Multiple Sclerosis Genetics Consortium et al. The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility
International Multiple Sclerosis Genetics Consortium et al. The Multiple Sclerosis Genomic Map: Role of
peripheral immune cells and resident microglia in susceptibility. BioRxiv. 2017. doi:10.1101/143933
Genetic and epigenetic fine mapping of causal autoimmune disease variants
- Kkh Farh
Farh KKH et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature.
2015;518:337-343.