Variation Of Multiple Sclerosis Research Articles

In silico prioritisation of microRNA-associated common variants in multiple sclerosis

BackgroundGenome-wide association studies (GWAS) have highlighted over 200 autosomal variants associated with multiple sclerosis (MS). However, variants in non-coding regions such as those encoding microRNAs have not been explored thoroughly, despite strong evidence of microRNA dysregulation in MS patients and model organisms. This study explores the effect of microRNA-associated variants in MS, through the largest publicly available GWAS, which involved 47,429 MS cases and 68,374 controls.MethodsWe identified SNPs within the coordinates of microRNAs, ± 5-kb microRNA flanking regions and predicted 3′UTR target-binding sites using miRBase v22, TargetScan 7.0 RNA22 v2.0 and dbSNP v151. We established the subset of microRNA-associated SNPs which were tested in the summary statistics of the largest MS GWAS by intersecting these datasets. Next, we prioritised those microRNA-associated SNPs which are among known MS susceptibility SNPs, are in strong linkage disequilibrium with the former or meet a microRNA-specific Bonferroni-corrected threshold. Finally, we predicted the effects of those prioritised SNPs on their microRNAs and 3′UTR target-binding sites using TargetScan v7.0, miRVaS and ADmiRE.ResultsWe have identified 30 candidate microRNA-associated variants which meet at least one of our prioritisation criteria. Among these, we highlighted one microRNA variant rs1414273 (MIR548AC) and four 3′UTR microRNA-binding site variants within SLC2A4RG (rs6742), CD27 (rs1059501), MMEL1 (rs881640) and BCL2L13 (rs2587100). We determined changes to the predicted microRNA stability and binding site recognition of these microRNA and target sites.ConclusionsWe have systematically examined the functional, structural and regulatory effects of candidate MS variants among microRNAs and 3′UTR targets. This analysis allowed us to identify candidate microRNA-associated MS SNPs and highlights the value of prioritising non-coding RNA variation in GWAS. These candidate SNPs could influence microRNA regulation in MS patients. Our study is the first thorough investigation of both microRNA and 3′UTR target-binding site variation in multiple sclerosis using GWAS summary statistics.

A multiple sclerosis-protective coding variant reveals an essential role for HDAC7 in regulatory T cells.

Genome-wide association studies identifying hundreds of susceptibility loci for autoimmune diseases indicate that genes active in immune cells predominantly mediate risk. However, identification and functional characterization of causal variants remain challenging. Here, we focused on the immunomodulatory role of a protective variant of histone deacetylase 7 (HDAC7). This variant (rs148755202, HDAC7.p.R166H) was identified in a study of low-frequency coding variation in multiple sclerosis (MS). Through transcriptomic analyses, we demonstrate that wild-type HDAC7 regulates genes essential for the function of Foxp3+ regulatory T cells (Tregs), an immunosuppressive subset of CD4 T cells that is generally dysfunctional in patients with MS. Moreover, Treg-specific conditional hemizygous deletion of HDAC7 increased the severity of experimental autoimmune encephalitis (EAE), a mouse model of neuroinflammation. In contrast, Tregs transduced with the protective HDAC7 R166H variant exhibited higher suppressive capacity in an in vitro functional assay, mirroring phenotypes previously observed in patient samples. In vivo modeling of the human HDAC7 R166H variant by generation of a knock-in mouse model bearing an orthologous R150H substitution demonstrated decreased EAE severity linked to transcriptomic alterations of brain-infiltrating Tregs, as assessed by single-cell RNA sequencing. Our data suggest that dysregulation of epigenetic modifiers, a distinct molecular class associated with disease risk, may influence disease onset. Last, our approach provides a template for the translation of genetic susceptibility loci to detailed functional characterization, using in vitro and in vivo modeling.

Whole-blood methylation signatures are associated with and accurately classify multiple sclerosis disease severity

BackgroundThe variation in multiple sclerosis (MS) disease severity is incompletely explained by genetics, suggesting genetic and environmental interactions are involved. Moreover, the lack of prognostic biomarkers makes it difficult for clinicians to optimise care. DNA methylation is one epigenetic mechanism by which gene–environment interactions can be assessed. Here, we aimed to identify DNA methylation patterns associated with mild and severe relapse-onset MS (RMS) and to test the utility of methylation as a predictive biomarker.MethodsWe conducted an epigenome-wide association study between 235 females with mild (n = 119) or severe (n = 116) with RMS. Methylation was measured with the Illumina methylationEPIC array and analysed using logistic regression. To generate hypotheses about the functional consequence of differential methylation, we conducted gene set enrichment analysis using ToppGene. We compared the accuracy of three machine learning models in classifying disease severity: (1) clinical data available at baseline (age at onset and first symptoms) built using elastic net (EN) regression, (2) methylation data using EN regression and (3) a weighted methylation risk score of differentially methylated positions (DMPs) from the main analysis using logistic regression. We used a conservative 70:30 test:train split for classification modelling. A false discovery rate threshold of 0.05 was used to assess statistical significance.ResultsFemales with mild or severe RMS had 1472 DMPs in whole blood (839 hypermethylated, 633 hypomethylated in the severe group). Differential methylation was enriched in genes related to neuronal cellular compartments and processes, and B-cell receptor signalling. Whole-blood methylation levels at 1708 correlated CpG sites classified disease severity more accurately (machine learning model 2, AUC = 0.91) than clinical data (model 1, AUC = 0.74) or the wMRS (model 3, AUC = 0.77). Of the 1708 selected CpGs, 100 overlapped with DMPs from the main analysis at the gene level. These overlapping genes were enriched in neuron projection and dendrite extension, lending support to our finding that neuronal processes, rather than immune processes, are implicated in disease severity.ConclusionRMS disease severity is associated with whole-blood methylation at genes related to neuronal structure and function. Moreover, correlated whole-blood methylation patterns can assign disease severity in females with RMS more accurately than clinical data available at diagnosis.

System-Level Variation in Multiple Sclerosis Disease-Modifying Therapy Utilization: Findings From the Multiple Sclerosis Continuous Quality Improvement Research Collaborative.

The Multiple Sclerosis Continuous Quality Improvement (MS-CQI) Collaborative is the first multicenter improvement research collaborative for multiple sclerosis (MS). The main objective of this study is to describe baseline system-level variation in disease-modifying therapy (DMT) utilization across 4 MS centers participating in MS-CQI. Electronic health record data from the first year of the 3-year MS-CQI study were analyzed. Participants were adults ≥ 18 years with MS presenting to any of the 4 MS-CQI centers. DMT utilization was categorized into oral, infusion, and injection types. Multinomial logistic regression was used to investigate associations between centers and DMT utilization. Overall, 2,029 patients were included in the analysis. Of those patients, 75.1% were female, mean age was 50 years, and 87.4% had relapsing-remitting MS. Overall, 32.7% were on an oral DMT, 23.5% on an infusion DMT, and 43.9% on an injection DMT. Overall, statistically significant differences (p < 0.01) were observed across centers for proportions of patients who received oral, infusion, and no DMTs. There were also overall significant differences (p < 0.01) across MS types for proportions of encounters who received oral, infusion, injection, no DMTs, and mean age varied significantly across centers. System-level effects on MS treatment and outcomes have not been previously studied and our findings contribute initial evidence concerning system-level variation in DMT utilization. Results suggest system-level variation in DMT utilization (ie, after adjusting for individual level factors, MS center or location of care a person with MS engages in care influences DMT treatment choices), resulting in a lack of standardization in DMT management. Continued research and improvement efforts targeting system-level performance could improve outcomes for people with MS.

Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis

The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family and 38 multiplex MS families and 44 sporadic MS cases and performed transcriptional and immunologic assessment of the identified variants. We identified a potentially causative homozygous missense variant in NLRP1 gene (Gly587Ser) in the primary family. Further possibly pathogenic NLRP1 variants were identified in the expanded cohort of patients. Stimulation of peripheral blood mononuclear cells from MS patients with putatively pathogenic NLRP1 variants showed an increase in IL-1B gene expression and active cytokine IL-1β production, as well as global activation of NLRP1-driven immunologic pathways. We report a novel familial association of MS and MM, and propose a possible underlying genetic basis in NLRP1 gene. Furthermore, we provide initial evidence of the broader implications of NLRP1-related pathway dysfunction in MS.

B7-H1 shapes T-cell–mediated brain endothelial cell dysfunction and regional encephalitogenicity in spontaneous CNS autoimmunity

Molecular mechanisms that determine lesion localization or phenotype variation in multiple sclerosis are mostly unidentified. Although transmigration of activated encephalitogenic T cells across the blood-brain barrier (BBB) is a crucial step in the disease pathogenesis of CNS autoimmunity, the consequences on brain endothelial barrier integrity upon interaction with such T cells and subsequent lesion formation and distribution are largely unknown. We made use of a transgenic spontaneous mouse model of CNS autoimmunity characterized by inflammatory demyelinating lesions confined to optic nerves and spinal cord (OSE mice). Genetic ablation of a single immune-regulatory molecule in this model [i.e., B7-homolog 1 (B7-H1, PD-L1)] not only significantly increased incidence of spontaneous CNS autoimmunity and aggravated disease course, especially in the later stages of disease, but also importantly resulted in encephalitogenic T-cell infiltration and lesion formation in normally unaffected brain regions, such as the cerebrum and cerebellum. Interestingly, B7-H1 ablation on myelin oligodendrocyte glycoprotein-specific CD4+ T cells, but not on antigen-presenting cells, amplified T-cell effector functions, such as IFN-γ and granzyme B production. Therefore, these T cells were rendered more capable of eliciting cell contact-dependent brain endothelial cell dysfunction and increased barrier permeability in an in vitro model of the BBB. Our findings suggest that a single immune-regulatory molecule on T cells can be ultimately responsible for localized BBB breakdown, and thus substantial changes in lesion topography in the context of CNS autoimmunity.

MtDNA T4216C variation in multiple sclerosis: a systematic review and meta-analysis.

MtDNA T4216C variation has frequently been investigated in Multiple Sclerosis (MS) patients; nonetheless, controversy has existed about the evidence of association of this variation with susceptibility to MS. The present systematic review and meta-analysis converge the results of the preceding publications, pertaining to association of mtDNA T4216C variation with susceptibility to MS, into a common conclusion. A computerized literature search in English was carried out to retrieve relevant publications from which required data were extracted. Using a fixed effect model, pooled odds ratio (OR), 95% confidence interval (95% CI), and P value were calculated for association of mtDNA T4216C variation with susceptibility to MS. The pooled results showed that there was a significant association between mtDNA T4216C variation and MS (OR=1.38, 95% CI=1.13-1.67, P=0.001). The present systematic review and meta-analysis suggest that mtDNA T4216C variation is a contributory factor in susceptibility to MS.

Mitochondrial DNA sequence variation in multiple sclerosis.

To assess the influence of common mitochondrial DNA (mtDNA) sequence variation on multiple sclerosis (MS) risk in cases and controls part of an international consortium. We analyzed 115 high-quality mtDNA variants and common haplogroups from a previously published genome-wide association study among 7,391 cases from the International Multiple Sclerosis Genetics Consortium and 14,568 controls from the Wellcome Trust Case Control Consortium 2 project from 7 countries. Significant single nucleotide polymorphism and haplogroup associations were replicated in 3,720 cases and 879 controls from the University of California, San Francisco. An elevated risk of MS was detected among haplogroup JT carriers from 7 pooled clinic sites (odds ratio [OR] = 1.15, 95% confidence interval [CI] = 1.07-1.24, p = 0.0002) included in the discovery study. The increased risk of MS was observed for both haplogroup T (OR = 1.17, 95% CI = 1.06-1.29, p = 0.002) and haplogroup J carriers (OR = 1.11, 95% CI = 1.01-1.22, p = 0.03). These haplogroup associations with MS were not replicated in the independent sample set. An elevated risk of primary progressive (PP) MS was detected for haplogroup J participants from 3 European discovery populations (OR = 1.49, 95% CI = 1.10-2.01, p = 0.009). This elevated risk was borderline significant in the US replication population (OR = 1.43, 95% CI = 0.99-2.08, p = 0.058) and remained significant in pooled analysis of discovery and replication studies (OR = 1.43, 95% CI = 1.14-1.81, p = 0.002). No common individual mtDNA variants were associated with MS risk. Identification and validation of mitochondrial genetic variants associated with MS and PPMS may lead to new targets for treatment and diagnostic tests for identifying potential responders to interventions that target mitochondria.

The Seasonal Variation of Multiple Sclerosis in Chile. A Study of Hospitalization Rates (P06.161)

Objective: To evaluate the seasonal variation of MS in Chile. Background The etiology of Multiple Sclerosis (MS) is probably determined by the likely interaction between genetic and environmental factors. Design/Methods: We studied hospital discharge G35 category of ICD-10 from 2001 to 2006 in 13 regions of the country. Specific rates were calculated for each season and were standardized to the 2002 Census population. A second analysis divided ing the year in Spring-Summer (SS) and Fall-Winter (FW). The differences were assessed with the two proportion test and ANOVA. Results: 6850 hospital discharges. Average hospitalization rate 0.20 (Confidence interval (CI), 0.13 to 0.27). There were no significant differences between national average rates when all seasons were analized. There were some regional differences. The Metropolitan Regions had the lowest rate in summer 1.24 (CI, 0.97 to 1.51) and the highest rate in Spring 1.49 (CI, 1.20 to 1.79). Regions XII had the highest rates, ranging from 1.94 (CI, -0.24, 4.12) in summer and 4.99 (CI, 1.49, 8.49) in winter. Statistically significant differences were found summer and winter rates in regions I, III and X, and between spring and fall rates in the II, VI, XI and XII regions. The average rates for SS an WF were 2.20 x 100.000 and 2.10, respectively, a statistical significant difference (p = 0.04). Significant differences were also found in the IV and Metropolitan regions (SS 0.89 and FW 2.16, p= 0.003 and a SS 2.64 and FW 2.54, p= 0.04 respectively) Conclusions: There was no clear seasonal trend of hospitalizations for MS in Chile as measured by hospital discharges when we analyzed the data by the four seasons but if analyzed with Spring-Summer and Fall-Winter a statistically significant average, country wide, higher rate of hospital admissions in Spring-Summer was found. Disclosure: Dr. Diaz has nothing to disclose. Dr. Barahona has nothing to disclose. Dr. Antinao has nothing to disclose. Dr. Silva has nothing to disclose. Dr. Parra has nothing to disclose. Dr. Olivares has nothing to disclose. Dr. Guiloff has nothing to disclose.

A seasonal periodicity in relapses of multiple sclerosis? A single-center, population-based, preliminary study conducted in Bologna, Italy

BackgroundTemporal, i.e., 24-hour, weekly, and seasonal patterns in the occurrence of acute cardiovascular and cerebrovascular events are well documented; however, little is known about temporal, especially seasonal, variation in multiple sclerosis (MS) and its relapses. This study investigated, by means of a validated chronobiological method, whether severe relapses of MS, ones requiring medical specialty consultation, display seasonal differences, and whether they are linked with seasonal differences in local meteorological variables.ResultsWe considered 96 consecutive patients with severe MS relapse (29 men, 67 women, mean age 38.5 ± 8.8 years), referred to the Multiple Sclerosis Center, Bellaria Hospital, Bologna, Italy, between January 1, 2007 and December 31, 2008. Overall, we analyzed 164 relapses (56 in men, 108 in women; 115 in patients aged < 40 years, 49 in patients ≥40 years). Relapses were more frequent in May and June (12.2% each) and the least frequent in September (3.7%). Chronobiological analysis showed a biphasic pattern (major peak in May-June, secondary peak in November-December, p = 0.030). Analysis of monthly mean meteorological data showed a significant seasonal pattern in ambient temperature (peak in July, p < 0.001), relative humidity (peak in January, p < 0.001), and wind speed (peak in June, p = 0.011).ConclusionsIn this Italian setting, we found a biphasic pattern (peaks in spring and autumn) in severe MS relapses requiring medical consultation by doctors of the MS specialty center, apparently unrelated to meteorological variables. Confirmations of the findings on larger multi-center populations residing in different climatic conditions are needed to further explore the potential seasonality of MS relapses and associated environmental triggers.

Monthly Ambient Sunlight, Infections and Relapse Rates in Multiple Sclerosis

Background: Monthly variation in multiple sclerosis (MS) relapses has been found. The relationship between seasonal environmental factors, infections, serum vitamin D [25(OH)D] and MS relapses is undetermined. Methods: We prospectively followed a population-based cohort of relapsing-remitting (RR) MS patients in Southern Tasmania for a mean 2.3 years (January 2002–April 2005). Associations between monthly ambient environmental factors, estimated serum 25(OH)D, upper respiratory tract (URT) infections and relapse rates were examined using weighted Pearson’s correlation and linear regression. Results: Of 199 definite MS patients, 142 had RRMS. The lowest relapse rate of 0.5 per 1,000 days (95% CI: 0.2–1.3) occurred in February (mid-late summer) versus the March–January RR of 1.1 per 1,000 days (95% CI: 0.9–1.3; p = 0.018, weighted regression). Monthly relapse rates correlated with: (1) prior erythemal ultraviolet radiation (EUV): lagged 1.5 months, r = –0.32, p = 0.046; (2) URT infection rate: no lag, r = 0.39, p = 0.014; (3) 25(OH)D: no lag, r = –0.31, p = 0.057. The association between URT infections and relapses was reduced after adjustment for monthly EUV. Conclusions: Relapse rates were inversely associated with EUV and serum 25(OH)D levels and positively associated with URT infections. The demonstrated lag between EUV but not 25(OH)D and relapse rates is consistent with a role for EUV-generated 25(OH)D in the alteration of relapse rates. Future work on the association between URT infections and relapses should be considered in the context of ultraviolet radiation and vitamin D.

APOE epsilon variation in multiple sclerosis susceptibility and disease severity

Previous studies have examined the role of APOE variation in multiple sclerosis (MS), but have lacked the statistical power to detect modest genetic influences on risk and disease severity. The meta- and pooled analyses presented here utilize the largest collection, to date, of MS cases, controls, and families genotyped for the APOE epsilon polymorphism. Studies of MS and APOE were identified by searches of PubMed, Biosis, Web of Science, Cochrane Review, and Embase. When possible, authors were contacted for individual genotype data. Meta-analyses of MS case-control data and family-based analyses were performed to assess the association of APOE epsilon genotype with disease risk. Pooled analyses of MS cases were also performed to assess the influence of APOE epsilon genotype on disease severity. A total of 22 studies (3,299 MS cases and 2,532 controls) were available for meta-analysis. No effect of epsilon2 or epsilon4 status on MS risk was observed (summary OR 1.14, 95% CI 0.96-1.34 and OR 0.89, 95% CI 0.78-1.01). Results obtained from analyses of APOE genotypes in 1,279 MS families were also negative (p = 0.61). Finally, results from pooled analyses of 4,048 MS cases also argue strongly that APOE epsilon status does not distinguish a relapsing-remitting from primary progressive disease course, or influence disease severity, as measured by the Expanded Disability Status Scale and disease duration. Overall, these findings do not support a role for APOE in multiple sclerosis, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.

Histo-clinical variation in multiple sclerosis: Heterogeneous proteolytic immunogenic processing

Multiple sclerosis (MS) presents an incredible histo-clinical variation. It consists of an unpredictable series of relapses, remissions and stationary phases. The initial symptoms vary considerably. Any hypothesis of the pathology of MS must include an explanation of this oddity. Current theory suggests that MS is a collection of diseases which produce generally the same result. However, this is not a satisfactory explanation. MS appears as an enormous continuum of disease paths rather than a finite group of well-defined courses. A hypothesis is presented that histo-clinical variation in MS is due to variable proteolytic processing of several potential immunogens. MS is generally thought to be caused by an autoimmune attack on myelin components. Several myelin proteins, myelin basic protein, lipoprotein, oligodendrocyte related glycoprotein and oligodendrocyte basic protein, are encephalitogenic. Within these proteins are short sequences, which themselves are encephalitogenic. In order for potential immunogens to be "seen" by the immune system they first must be processed. This processing is performed by intracellular and extracellular proteases. A large number of different proteases are located throughout the central nervous system. Their concentrations vary with location and time. Most are under strict control. While myelin has a consistent structure, the action of proteases can present variable concentrations of immunogenic peptides. Because of the differences in location, concentration and control of the central nervous system's (CNS) proteases, the same potential immunogen could be presented to the immune system in different locations within the CNS at different times. At a given time and location, the immune system may be presented with no potential immunogens, one potential immunogen or possibly many immunogens. Therefore, because of the dynamic characteristic of presentation, one would expect to see the initial MS symptoms to be variable. This variability would be continued with subsequent symptoms. This is what is seen in multiple sclerosis. A procedure for testing this hypothesis is presented.