Multiple sclerosis risk variants alter expression of co-stimulatory genes in B cells

Smets, Ide; Fiddes, Barnaby; Garcia-Perez, Josselyn E.; He, Di; Mallants, Klara; Liao, Wenjia; Dooley, James; Wang, George; Humblet-Baron, Stéphanie; Dubois, Bénédicte; Compston, Alastair; Jones, Joanne L.; Coles, Alasdair; Liston, Adrian; Ban, Masashi; Goris, An; Sawcer, Stephen

doi:10.1093/brain/awx372

Cited by 39 publications

(33 citation statements)

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“…In this report we combine the latest IMSGC GWAS data with large mQTL and eQTL datasets and a list of curated 'druggable genes' to provide a data-driven list of 45 prioritised drug targets for multiple sclerosis. Three of these targets -CD40, MERTK, and PARP1 -have strong evidence to support a biological causal relationship between genetic variation, 25,26 , an effect which is replicated in our study (Beta SMR -0.50, p SMR = 1.89x10 -12 ). In a study of PBMCs from people with MS and healthy controls, the susceptibility SNP rs4810485 was associated with both alternative splicing of CD40 transcripts -with relative upregulation of the splice isoform lacking exon 5 leading to lower cell-surface expressionand with lower levels of the anti-inflammatory cytokine IL-10 in peripheral blood 26 .…”

Section: Discussionsupporting

confidence: 76%

“…Three of these targets -CD40, MERTK, and PARP1 -have strong evidence to support a biological causal relationship between genetic variation, 25,26 , an effect which is replicated in our study (Beta SMR -0.50, p SMR = 1.89x10 -12 ). In a study of PBMCs from people with MS and healthy controls, the susceptibility SNP rs4810485 was associated with both alternative splicing of CD40 transcripts -with relative upregulation of the splice isoform lacking exon 5 leading to lower cell-surface expressionand with lower levels of the anti-inflammatory cytokine IL-10 in peripheral blood 26 . These data suggest that genetically-determined modulation of CD40 mRNA expression may promote MS risk via effects of alternatively-spliced transcripts on IL-10 production, although the exact mechanism remains to be clarified.…”

Section: Discussionsupporting

confidence: 76%

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Summary-data-based mendelian randomisation reveals druggable targets for multiple sclerosis

Jacobs

Taylor

Awad

et al. 2020

Preprint

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Background:Multiple Sclerosis (MS) is a complex autoimmune disease caused by a combination of genetic and environmental factors. Translation of Genome-Wide Association Study (GWAS) findings in MS into therapeutics and effective preventive strategies has been limited to date. Methods:We used Summary Data-Based Mendelian Randomisation (SMR) to synthesise findings from public expression quantitative trait locus (eQTL; eQTLgen and CAGE), methylation quantitative trait locus (mQTL; Lothian Birth Cohort and Brisbane Systems Genetics Study), and MS GWAS datasets (International Multiple Sclerosis Genetics Consortium). By correlating the effects of methylation on MS (M-2-MS), methylation on expression (M-2-E), and expression on MS susceptibility (E-2-MS), we prioritise genetic loci with strong evidence of causally influencing MS susceptibility. We overlay these findings onto a list of 'druggable' genes, i.e. genes which are currently, or could theoretically, be targeted by therapeutic compounds. We use GeNets and STRING to identify protein-protein interactions and druggable pathways enriched in our results. We extend these findings to a model of Epstein-Barr Virus-infected B cells, Lymphoblastoid Cell Lines (LCLs). We conducted a systematic review of prioritised genes using the Open Targets platform to identify completed and planned trials targeted prioritised genes in MS and related disease areas. Results:Expression of 45 genes in peripheral was strongly associated with MS susceptibility (False discovery rate 0.05). Of these 45 genes, 20 encode a protein which is currently targeted by an existing therapeutic compound. These genes were enriched for Gene Ontology terms pertaining to immune system function and leukocyte signalling. We refined this prioritised gene list by restricting to loci where CpG site methylation was associated with MS susceptibility (M-2-MS), with gene expression (M-2-E), and where expression was associated with MS susceptibility (E-2-MS). This approach yielded a list of 15 prioritised druggable target genes for which there was evidence of a causal pathway linking methylation, expression, and MS. Five of these 15 genes are targeted by existing drugs (CD40, ERBB2, VEGFB, MERTK, and PARP1), and three were replicated in a smaller eQTL dataset (CD40, MERTK, and PARP1). In LCLs, SMR prioritised 7 druggable gene targets, of which only one was priortised by the multi-omic approach in peripheral blood (FCRL3). Systematic review of Open Targets revealed multiple early-phase trials targeting 13/20 prioritised genes in disorders related to MS. Conclusions:We use public datasets and SMR to identify a list of prioritised druggable genetic targets in Multiple Sclerosis. We hope our findings could be translated into effective repurposing of existing drugs to provide novel therapies for MS and, potentially, provide a platform for developing preventive therapies.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionsupporting

confidence: 76%

Summary-data-based mendelian randomisation reveals druggable targets for multiple sclerosis

Jacobs

Taylor

Awad

et al. 2020

Preprint

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“…One previous study describes a clear sex dependent difference in CD80 expression on B cells in neuroinflammatory diseases, independent on disease severity [26]. There is a CD86 polymorphism resulting in higher CD86 expression on B cells [27], and it cannot be excluded that there was an increased frequency of men with that allele in our cohort. It will be interesting to see if our surprising finding will be confirmed by others.…”

Section: Discussionmentioning

confidence: 66%

A combination of the activation marker CD86 and the immune checkpoint marker B and T lymphocyte attenuator (BTLA) indicates a putative permissive activation state of B cell subtypes in healthy blood donors independent of age and sex

et al. 2020

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Background: The use of anti-B cell based therapies in immune-mediated diseases targeting general B cell markers or molecules important for B cell function has increased the clinical needs of monitoring B cell subpopulations. Results: We analyzed the expression profile of cell surface markers CD86 and B and T lymphocyte attenuator (BTLA) in B cell subtypes using flow cytometry, including naïve, transitional, switched memory, non-switched memory and double-negative memory B cells and plasmablasts, and investigated the dependence of age and sex in a healthy adult blood donor population. The switched memory B cell subtype displayed a divergent expression of the markers, with increased CD86 and decreased BTLA as compared to non-switched and double negative memory cells, as well as compared to naïve B cells. Plasmablasts expressed highly increased CD86 compared to all other subtypes and a decreased expression of BTLA compared to naïve cells, but still higher compared to the memory cell populations. Transitional B cells had CD86 and BTLA expression similar to the other naïve cells. Conclusions: We show divergent expression of CD86 and BTLA in memory cells and plasmablasts compared to naïve B cells independent of age and sex. Furthermore, a similarly divergent difference of expression pattern was seen between the memory cell subtypes, altogether indicating that the combination of CD86 and BTLA might be markers for a permissive activation state. We suggest the combination of CD86 and BTLA expression on B cell subtypes as a potentially important tool in monitoring the status of B cell subtypes before and after treatments influencing the B cell compartment.

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“…There was an increased frequency of transitional B cells detected in people with CIS compared with HC ( 18 ); transitional B cells in this study had some identifying characteristics congruent with the functionally immature B cell phenotype reported to have limited capacity for Ig production ( 37 ). Given the importance of CD40 for class switching to occur in germinal centers ( 38 ), and the finding of decreased B cell CD40 expression in association with the MS risk allele rs4810485*T ( 39 ), we suggest that there may be impairment of normal class switching in CIS and MS mediated, in part, by a reduction in CD40–CD40L engagement on maturing B cells.…”

Section: Discussionmentioning

confidence: 94%

Higher Serum Immunoglobulin G3 Levels May Predict the Development of Multiple Sclerosis in Individuals With Clinically Isolated Syndrome

et al. 2018

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Clinically isolated syndrome (CIS) is a first episode of neurological symptoms that may precede a diagnosis of multiple sclerosis (MS). Therefore, studying individuals with CIS may lead to breakthroughs in understanding the development and pathogenesis of MS. In this study, serum levels of immunoglobulin (Ig)G, IgA, IgM, and IgG1–4 were measured in 20 people with CIS and compared with those in 10 healthy controls (HC) and 8 people with MS. Serum Ig levels in individuals with CIS were compared with (a) the time to their conversion from CIS to MS, (b) serum levels of antibodies to Epstein–Barr virus, (c) frequencies of T regulatory (Treg), T follicular regulatory (Tfr), and B cell subsets, and (d) Treg/Tfr expression of Helios. Serum IgG, IgM, and IgG2 levels were significantly lower in people with CIS than HC, and IgG, IgM, and IgG1 levels were significantly lower in people with CIS than MS. After adjusting for age, sex, and serum 25(OH) vitamin D3 [25(OH)D] levels, CIS was associated with lower serum levels of IgG and IgG2 compared with HC (p = 0.001 and p < 0.001, respectively). People with MS had lower IgG2 levels (p < 0.001) and IgG2 proportions (%IgG; p = 0.007) compared with HC. After adjusting for age, sex, and 25(OH)D, these outcomes remained, in addition to lower serum IgA levels (p = 0.01) and increased IgG3 levels (p = 0.053) in people with MS compared with HC. Furthermore, serum from people with MS had increased proportions of IgG1 and IgG3 (p = 0.03 and p = 0.02, respectively), decreased proportions of IgG2 (p = 0.007), and greater ratios of “upstream” to “downstream” IgG subclasses (p = 0.001) compared with HC. Serum IgG3 proportions (%IgG) from people with CIS correlated with the frequency of plasmablasts in peripheral blood (p = 0.02). Expression of Helios by Treg and Tfr cell subsets from individuals with CIS correlated with levels of serum IgG2 and IgG4. IgG3 levels and proportions of IgG3 (%IgG) in serum at CIS diagnosis were inversely correlated with the time until conversion to MS (p = 0.018 and p < 0.001, respectively), suggesting they may be useful prognostic markers of individuals with CIS who rapidly convert to MS.

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Multiple sclerosis risk variants alter expression of co-stimulatory genes in B cells

Cited by 39 publications

References 44 publications

Summary-data-based mendelian randomisation reveals druggable targets for multiple sclerosis

Summary-data-based mendelian randomisation reveals druggable targets for multiple sclerosis

A combination of the activation marker CD86 and the immune checkpoint marker B and T lymphocyte attenuator (BTLA) indicates a putative permissive activation state of B cell subtypes in healthy blood donors independent of age and sex

Higher Serum Immunoglobulin G3 Levels May Predict the Development of Multiple Sclerosis in Individuals With Clinically Isolated Syndrome

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