Factors In Multiple Sclerosis Research Articles

Identification of crucial inflammaging related risk factors in multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory demyelinating lesions in the central nervous system. Studies have shown that the inflammation is vital to both the onset and progression of MS, where aging plays a key role in it. However, the potential mechanisms on how aging-related inflammation (inflammaging) promotes MS have not been fully understood. Therefore, there is an urgent need to integrate the underlying mechanisms between inflammaging and MS, where meaningful prediction models are needed. First, both aging and disease models were developed using machine learning methods, respectively. Then, an integrated inflammaging model was used to identify relative risk factors, by identifying essential "aging-inflammation-disease" triples. Finally, a series of bioinformatics analyses (including network analysis, enrichment analysis, sensitivity analysis, and pan-cancer analysis) were further used to explore the potential mechanisms between inflammaging and MS. A series of risk factors were identified, such as the protein homeostasis, cellular homeostasis, neurodevelopment and energy metabolism. The inflammaging indices were further validated in different cancer types. Therefore, various risk factors were integrated, and even both the theories of inflammaging and immunosenescence were further confirmed. In conclusion, our study systematically investigated the potential relationships between inflammaging and MS through a series of computational approaches, and could present a novel thought for other aging-related diseases.

Correlation between antibodies against the pathogenic pHERV-W envelope protein and the inflammatory phase of multiple sclerosis.

The role of retroviral envelope proteins belonging to the Human Endogenous Retroviral family 'W' (HERV-W), specifically syncytin-1 and pathogenic HERV-W (pHERV-W), as potential risk factors in multiple sclerosis (MS) has been established. This study aimed to investigate the humoral response to syncytin-1 and pHERV-W-derived peptides in a group of relapsing remitting MS patients categorized as having acute or stable disease. Furthermore, an inhibition assay was conducted to assess the extent of cross-reactivity between the two epitopes. The findings revealed that MS patients in the acute phase exhibited a higher specific antibody response to the pHERV-W env epitope compared to syncytin-1. This suggests a potential pathogenic role for pHERV-W env during the inflammatory stages of central nervous system involvement, and these antibody responses could serve as useful biomarkers for monitoring the progression of the disease.

Investigation of polymorphism tumor necrosis factor in multiple sclerosis: A Systematic Review and Meta-Analysis

Multiple sclerosis (MS) is an acquired disabling neurological disease of young adults, affecting approximately 2.3 million people worldwide. Multiple sclerosis is an inflammatory disease of the central nervous system (CNS), which causes a heterogeneous array of symptoms and signs because of the differential involvement of motor, sensory, visual, and autonomic systems. TNF-α is an important cytokine of the inflammatory response involved in the pathogenesis of multiple sclerosis. A systematic literature review and a meta-analysis were conducted to discuss the tumor necrosis factor-α (TNF-α) polymorphism and prognosis of MS. PubMed and Embase databases were searched to find articles published between January 2000 and December 2022. Forty eligible studies, comprising 4220 patients with MS and 5321 controls, were included in the meta-analysis. In most populations, the pooled ORs (95%CI) for TNF 2/1 versus 1/1 were 0.95 (0.82-0.99), the pooled ORs (95%CI) for TNF 2/1 versus 1/1 and TNF 2/2 versus 2/1 were not statistically significant in the overall population. In conclusion, the data from this meta-analysis study show no significant role of TNF-α polymorphism in multiple sclerosis.

Multi-Criterial Model for Weighting Biological Risk Factors in Multiple Sclerosis: Clinical and Health Insurance Implications.

The etiology of Multiple Sclerosis (MS) remains undetermined. Its pathogenic risk factors are thought to play a negligible role individually in the development of the disease, instead assuming a pathogenic role when they interact with each other. Unfortunately, the statistical weighting of this pathogenic role in predicting MS risk is currently elusive, preventing clinical and health insurance applications. Here, we aim to develop a population-based multi-criterial model for weighting biological risk factors in MS; also, to calculate the individual MS risk value useful for health insurance application. Accordingly, among 596 MS patients retrospectively assessed at the time of diagnosis, the value of vitamin D < 10 nm/L, BMI (Body Mass Index) < 15 Kg/m2 and >30 Kg/m2, female sex, degree of family kinship, and the range of age at onset of 20-45 years were considered as biological risk factors for MS. As a result, in a 30-year-old representative patient having a BMI of 15 and second degree of family kinship for MS, the major developmental contributor for disease is the low vitamin D serum level of 10 nm/L, resulting in an MS risk of 0.110 and 0.106 for female and male, respectively. Furthermore, the Choquet integral applied to uncertain variables, such as biological risk factors, evidenced the family kinship as the main contributor, especially if coincident with the others, to the MS risk. This model allows, for the first time, for the risk stratification of getting sick and the application of the health insurance in people at risk for MS.

Novel nano-carriers with N-formylmethionyl-leucyl-phenylalanine-modified liposomes improve effects of C16-angiopoietin 1 in acute animal model of multiple sclerosis

Gradual loss of neuronal structure and function due to impaired blood–brain barrier (BBB) and neuroinflammation are important factors in multiple sclerosis (MS) progression. Our previous studies demonstrated that the C16 peptide and angiopoietin 1 (Ang-1) compound (C + A) could modulate inflammation and vascular protection in many models of MS. In this study, nanotechnology and a novel nanovector of the leukocyte chemotactic peptide N-formyl-methionyl-leucyl–phenylalanine (fMLP) were used to examine the effects of C + A on MS. The acute experimental autoimmune encephalomyelitis (EAE) model of MS was established in Lewis rats. The C + A compounds were conjugated to control nano-carriers and fMLP-nano-carriers and administered to animals by intravenous injection. The neuropathological changes in the brain cortex and spinal cord were examined using multiple approaches. The stimulation of vascular injection sites was examined using rabbits. The results showed that all C + A compounds (C + A alone, nano-carrier C + A, and fMLP-nano-carrier C + A) reduced neuronal inflammation, axonal demyelination, gliosis, neuronal apoptosis, vascular leakage, and BBB impairment induced by EAE. In addition, the C + A compounds had minimal side effects on liver and kidney functions. Furthermore, the fMLP-nano-carrier C + A compound had better effects compared to C + A alone and the nano-carrier C + A. This study indicated that the fMLP-nano-carrier C + A could attenuate inflammation-related pathological changes in EAE and may be a potential therapeutic strategy for the treatment of MS and EAE.

Cholecalciferol Supplementation Induced Up-Regulation of SARAF Gene and Down-Regulated miR-155-5p Expression in Slovenian Patients with Multiple Sclerosis.

Multiple sclerosis is a common immune-mediated inflammatory and demyelinating disease. Lower cholecalciferol levels are an established environmental risk factor in multiple sclerosis. Although cholecalciferol supplementation in multiple sclerosis is widely accepted, optimal serum levels are still debated. Moreover, how cholecalciferol affects pathogenic disease mechanisms is still unclear. In the present study, we enrolled 65 relapsing-remitting multiple sclerosis patients who were double-blindly divided into two groups with low and high cholecalciferol supplementation, respectively. In addition to clinical and environmental parameters, we obtained peripheral blood mononuclear cells to analyze DNA, RNA, and miRNA molecules. Importantly, we investigated miRNA-155-5p, a previously published pro-inflammatory miRNA in multiple sclerosis known to be correlated to cholecalciferol levels. Our results show a decrease in miR-155-5p expression after cholecalciferol supplementation in both dosage groups, consistent with previous observations. Subsequent genotyping, gene expression, and eQTL analyses reveal correlations between miR-155-5p and the SARAF gene, which plays a role in the regulation of calcium release-activated channels. As such, the present study is the first to explore and suggest that the SARAF miR-155-5p axis hypothesis might be another mechanism by which cholecalciferol supplementation might decrease miR-155 expression. This association highlights the importance of cholecalciferol supplementation in multiple sclerosis and encourages further investigation and functional cell studies.

Vascular disease risk factors in multiple sclerosis: Effect on metabolism and brain volumes.

Vascular disease risk factors (VDRF) such as hypertension, hyperlipidemia, obesity, diabetes and heart disease likely play a role in disease progression in people with multiple sclerosis (PwMS) (Marrie, Rudick etal. 2010). Studies exploring the mechanistic connection between vascular disease and MS disease progression are scant. We hypothesized that phosphate energy metabolism impairment in PwMS with VDRFs (VDRF+) will be greater compared to PwMS without VDRFs (VDRF-) and is related to increased brain atrophy in VDRF+. To test this hypothesis, we planned to study the differences in the high energy phosphate (HEP) metabolites in cerebral gray matter as assessed by 31P magnetic resonance spectroscopic imaging (MRSI) and MRI brain volumetric in the VDRF+ and VDRF- PwMS at four different timepoints over a 3 yearlong period using a 7T MR system. We present here the results from the cross-sectional evaluation of HEP metabolites and brain volumes. We also evaluated the differences in clinical impairment, blood metabolic biomarkers and quality of life in VDRF+ and VDRF- PwMS in this cohort. Group differences in high energy phosphate metabolites were assessed from a volume of interest in the occipital region using linear mixed models. Brain parenchymal and white matter lesion volumes were determined from MR anatomic images. We present here the cross-sectional analysis of the baseline data collected as part of a longitudinal 3 yearlong study where we obtained baseline and subsequent 6-monthly clinical and laboratory data and annual 7T MRI volumetric and 31P MR spectroscopic imaging (MRSI) data on 52 PwMS with and without VDRF. Key clinical and laboratory outcomes included: body mass index (BMI), waist and thigh circumferences and disability [Expanded Disability Status Scale (EDSS)], safety (complete blood count with differential, complete metabolic), lipid panel including total cholesterol and HbA1C. We analyzed clinical and laboratory data for the group differences using student's t or χ2 test. We investigated relationship between phosphate metabolites and VDRF using mixed effect linear regression. Complete MRI data were available for 29 VDRF+, age 56.3 (6.8) years [mean (SD)] (83% female), and 23 VDRF-, age 52.5 (7.5) years (57% female) individuals with MS. The mean value of normalized adenosine triphosphate (ATP) (calculated as the ratio of ATP to total phosphate signal in a voxel) was decreased by 4.5% (p < .05) in VDRF+ compared to VDRF- MS group. White matter lesion (WML) volume fraction in VDRF+ individuals {0.007 (0.007)} was more than doubled compared to VDRF- participants {0.003 (0.006), p= .02}. We found significantly lower brain ATP and higher inorganic phosphate (Pi) in those PwMS with VDRFs compared to those without. ATP depletion may reflect mitochondrial dysfunction. Ongoing longitudinal data analysis from this study, not presented here, will evaluate the relationship of phosphate metabolites, brain atrophy and disease progression in PwMS with and without vascular disease.

The immunomodulatory phenomenon of vitamin D in the pathogenesis of Multiple Sclerosis

People living in areas with limited access to sunlight, do not produce enough vitamin D and are more likely to suffer from Multiple Sclerosis.Near the equator, where there is high exposure to the sun, the disease is almost non-existent. Aim of the study: The study aimto statistical data on the literature and presents the current state of Vitamin D deficiency as a risk factor in multiple sclerosis. Material and method: The method of study is descriptive epidemiological analysis. Information that has been used is derived from statistical data provided by the WHO. In searching for them on the WHO, PubMed website, Google Scholar, and SCOPUS. Results and conclusions: Vitamin D is a regulator of calcium and phosphorus levels and affects the development and proper functioning of the nervous system. Patients with Multiple sclerosis often have low serum vitamin D levels, which tend to decrease as the disease progresses. There are theories that a deficiency of this vitamin promotes autoimmune, inflammatory demyelination.

Lifestyle and Environmental Factors in Multiple Sclerosis

Lifestyle and Environmental Factors in Multiple Sclerosis

Multiple Sclerosis and Sodium Toxicity: Controversy and Future Directions for Low-Salt Interventions

Salt intake is associated with multiple sclerosis; however, controversial findings that challenge this association rely primarily on methods that do not measure total sodium storage within the body, such as food surveys and urinary sodium excretion. In contrast, tissue sodium concentrations measured with sodium MRI confirm high sodium levels in multiple sclerosis, suggesting a role for sodium toxicity as a risk factor for the disease. Research on demyelination in the central nervous system has identified myelin phase transitions associated with increased salinity, which cause structural instabilities of myelin sheaths and add further evidence implicating sodium toxicity as a causative factor in multiple sclerosis. Inflammatory and immune responses in multiple sclerosis are also related to high sodium intake. In addition, salt is a potential mediating factor associating multiple sclerosis with comorbidities, including systemic lupus erythematosus, rheumatic arthritis, inflammatory bowel disease, and cardiovascular disease. Current confusion exists over classifying dietary sodium intake levels as low, normal, and high, and questions remain over levels of sodium restriction necessary for disease prevention. To reduce multiple sclerosis symptoms and prevent disease progression in patients, future research should investigate low-salt interventions with levels of sodium intake associated with ancestral hunter-gatherer tribes.

Ocrelizumab Treatment Modulates B-Cell Regulating Factors in Multiple Sclerosis.

Antibodies to CD20 efficiently reduce new relapses in multiple sclerosis (MS), and ocrelizumab has been shown to be effective also in primary progressive MS. Although anti-CD20 treatments efficiently deplete B cells in blood, some B cells and CD20- plasma cells persist in lymphatic organs and the inflamed CNS; their survival is regulated by the B cell-activating factor (BAFF)/A proliferation-inducing ligand (APRIL) system. The administration of a soluble receptor for BAFF and APRIL, atacicept, unexpectedly worsened MS. Here, we explored the long-term effects of ocrelizumab on immune cell subsets as well as on cytokines and endogenous soluble receptors comprising the BAFF-APRIL system. We analyzed immune cell subsets and B cell-regulating factors longitudinally for up to 2.5 years in patients with MS treated with ocrelizumab. In a second cohort, we determined B-cell regulatory factors in the CSF before and after ocrelizumab. We quantified the cytokines BAFF and APRIL along with their endogenous soluble receptors soluble B-cell maturation antigen (sBCMA) and soluble transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (sTACI) using enzyme-linked immunosorbent assays (ELISAs). In addition, we established an in-house ELISA to measure sTACI-BAFF complexes. Ocrelizumab treatment of people with MS persistently depleted B cells and CD20+ T cells. This treatment enhanced BAFF and reduced the free endogenous soluble receptor and decoy sTACI in both serum and CSF. Levels of sTACI negatively correlated with BAFF levels. Reduction of sTACI was associated with formation of sTACI-BAFF complexes. We describe a novel effect of anti-CD20 therapy on the BAFF-APRIL system, namely reduction of sTACI. Because sTACI is a decoy for APRIL, its reduction may enhance local APRIL activity, thereby promoting regulatory IgA+ plasma cells and astrocytic interleukin (IL)-10 production. Thus, reducing sTACI might contribute to the beneficial effect of anti-CD20 as exogenous sTACI (atacicept) worsened MS. This study provides Class IV evidence that endogenous sTACI in blood and CSF is decreased after ocrelizumab treatment.

Estrogen receptor alpha signaling in dendritic cells modulates autoimmune disease phenotype in mice.

Estrogen is a disease-modifying factor in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) via estrogen receptor alpha (ERα). However, the mechanisms by which ERα signaling contributes to changes in disease pathogenesis have not been completely elucidated. Here, we demonstrate that ERα deletion in dendritic cells (DCs) of mice induces severe neurodegeneration in the central nervous system in a mouse EAE model and resistance to interferon beta (IFNβ), a first-line MS treatment. Estrogen synthesized by extragonadal sources is crucial for controlling disease phenotypes. Mechanistically, activated ERα directly interacts with TRAF3, a TLR4 downstream signaling molecule, to degrade TRAF3 via ubiquitination, resulting in reduced IRF3 nuclear translocation and transcription of membrane lymphotoxin (mLT) and IFNβ components. Diminished ERα signaling in DCs generates neurotoxic effector CD4+ T cells via mLT-lymphotoxin beta receptor (LTβR) signaling. Lymphotoxin beta receptor antagonist abolished EAE disease symptoms in the DC-specific ERα-deficient mice. These findings indicate that estrogen derived from extragonadal sources, such as lymph nodes, controls TRAF3-mediated cytokine production in DCs to modulate the EAE disease phenotype.

Comparing RNA-sequencing datasets from astrocytes, oligodendrocytes, and microglia in multiple sclerosis identifies novel dysregulated genes relevant to inflammation and myelination.

Central nervous system (CNS) inflammation is a key factor in multiple sclerosis (MS). Invasion of peripheral immune cells into the CNS resulting from an unknown signal or combination of signals results in activation of resident immune cells and the hallmark feature of the disease: demyelinating lesions. These lesion sites are an amalgam of reactive peripheral and central immune cells, astrocytes, damaged and dying oligodendrocytes, and injured neurons and axons. Sustained inflammation affects cells directly located within the lesion site and further abnormalities are apparent diffusely throughout normal-appearing white matter and grey matter. It is only relatively recently, using animal models, new tissue sampling techniques, and next-generation sequencing, that molecular changes occurring in CNS resident cells have been broadly captured. Advances in cell isolation through Fluorescence Activated Cell Sorting (FACS) and laser-capture microdissection together with the emergence of single-cell sequencing have enabled researchers to investigate changes in gene expression in astrocytes, microglia, and oligodendrocytes derived from animal models of MS as well as from primary patient tissue. The contribution of some dysregulated pathways has been followed up in individual studies; however, corroborating results often go unreported between sequencing studies. To this end, we have consolidated results from numerous RNA-sequencing studies to identify and review novel patterns of differentially regulated genes and pathways occurring within CNS glial cells in MS. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology.

Analysis of herpesvirus infection and genome single nucleotide polymorphism risk factors in multiple sclerosis, Volga federal district, Russia.

Multiple sclerosis (MS) is a heterogeneous disease where herpesvirus infection and genetic predisposition are identified as the most consistent risk factors. Serum and blood samples were collected from 151 MS and 70 controls and used to analyze circulating antibodies for, and DNA of, Epstein Barr virus (EBV), human cytomegalovirus (HCMV), human herpes virus 6 (HHV6), and varicella zoster virus (VZV). The frequency of selected single nucleotide polymorphisms (SNPs) in MS and controls were studied. Herpesvirus DNA in blood samples were analyzed using qPCR. Anti-herpesvirus antibodies were detected by ELISA. SNPs were analyzed by the allele-specific PCR. For statistical analysis, Fisher exact test, odds ratio and Kruskall-Wallis test were used; p<0.05 values were considered as significant. We have found an association between circulating anti-HHV6 antibodies and MS diagnosis. We also confirmed higher frequency of A and C alleles in rs2300747 and rs12044852 of CD58 gene and G allele in rs929230 of CD6 gene in MS as compared to controls. Fatigue symptom was linked to AC and AA genotype in rs12044852 of CD58 gene. An interesting observation was finding higher frequency of GG genotype in rs12722489 of IL2RA and T allele in rs1535045 of CD40 genes in patient having anti-HHV6 antibodies. A link was found between having anti-VZV antibodies in MS and CC genotype in rs1883832 of CD40 gene.

Environmental Risk Factors in Multiple Sclerosis: A Narrative Review

Background Multiple sclerosis (MS) is one of the chronic autoimmune diseases and a progressive disease of the central nervous system that have unknown causes. Objective This study aims to review the environmental risk factors of MS. Methods In this review study, a search was conducted in databases such as PubMed, Scopus, ScienceDirect, Google Scholar and MagIran on related studies published in Persian and English from 2000 to 2021 using the keywords: Multiple Sclerosis, MS, Environmental risk factors, and Epidemiology. Results The studies showed that MS is an autoimmune disease with unknown genetic backgrounds. The age of 20-40 years, female gender, distance from the equator, migration, Epstein-Barr virus infection, smoking, air pollution, vitamin D deficiency, alcohol and coffee consumption, circadian disruption, and psychological factors are the environmental risk factors of MS. Conclusion Given the environmental risk factors of MS, their control is potentially helpful in preventing the disease and its rapid progression. It is necessary for health care providers to pay attention to these risk factors.

Association between Genetic Polymorphisms in Methylenetetrahydrofolate Reductase and Risk of Autoimmune Diseases: A Systematic Review and Meta-Analysis.

Methylenetetrahydrofolate reductase (MTHFR) is a critical rate-limiting enzyme in the homocysteine/methionine metabolism pathway that is implicated in the pathogenesis and progression of autoimmune diseases. Previous association studies have been performed to investigate the effect of polymorphisms in MTHFR on the risk of autoimmune diseases with inconsistent results. Therefore, this meta-analysis was designed to assess the association between the MTHFR 677 C/T and 1298 A/C polymorphisms and the susceptibility to autoimmune diseases. We identified reports by a literature search in the following electronic databases: PubMed, Ovid, Web of science, and China National Knowledge Infrastructure. Statistical analyses of the summary odds ratios (ORs) and 95% confidence intervals (CIs) were done using STATA software. In a recessive genetic model, the MTHFR 677 C/T polymorphism was associated with an increased risk of Behcet's disease (OR = 1.97, 95% CI, 1.31-2.97), multiple sclerosis (OR = 1.57, 95% CI, 1.03-2.38), and ankylosing spondylitis (OR = 2.90, 95% CI, 1.92-4.38). The MTHFR 1298 A/C polymorphism was associated an increased risk of multiple sclerosis in a heterozygote comparison (OR = 2.36, 95% CI, 1.29-4.30) and in a dominant model (OR = 2.31, 95% CI, 1.24-4.29). This meta-analysis demonstrated that the MTHFR 677 C/T was a risk factor for Behcet's disease, multiple sclerosis, and ankylosing spondylitis, and the 1298 A/C was a risk factor for multiple sclerosis.

The most effective sexual function and dysfunction interventions in individuals with multiple sclerosis: A systematic review and meta-analysis.

BackgroundSexual dysfunction has many factors in multiple sclerosis, but there is no reliable treatment for this challenge. ObjectiveDetermining effective sexual function or dysfunction interventions in individuals with multiple sclerosis.Materials and MethodsTo find the relevant published interventional studies that at least had an English abstract or in Persian, we searched International Statistical Institute, PubMed, Scopus, Cochrane, Medline, PsycINFO, EMBASE, CINAHL, and Google Scholar from January 1990 to June 2021. The results were analyzed using RevMan 5.3 software. The p 0.05 was considered significant.ResultsOut of 568 articles, 41 were included after deleting the duplicate and irrelevant articles. Studies were divided into 2 groups of sexual function (n = 27) and dysfunction (n = 14). Interventions in each category have 4 subgroups: psychoeducational, exercise and rehabilitation, and medical and multi-type interventions. For improving sexual function, more than half of psychoeducational interventions showed a significant improvement after interventions (p = 0.0003). In sexual dysfunction studies, most of the interventions (n = 13/14) had improved at least one subscale of sexual dysfunction. Medical interventions were effective on men's sexual dysfunction, and psychoeducational interventions had been more effective in women's sexual dysfunction.ConclusionPsychoeducational and medical interventions are the commonest effective interventions. The psychoeducational studies conducted specifically on women had a positive impact, and only 4 articles with medical interventions were specifically targeted at men, which had a positive effect.

Endothelial ETS1 inhibition exacerbate blood–brain barrier dysfunction in multiple sclerosis through inducing endothelial-to-mesenchymal transition

Blood–brain barrier (BBB) dysfunction has been recognized as an early pathological feature and contributing factor in multiple sclerosis. Endothelial-to-mesenchymal transition is a process associated with endothelial dysfunction leading to the disruption of vessel stability and barrier function, yet its functional consequence in multiple sclerosis remains unclear. Here, we demonstrated that endothelial-to-mesenchymal transition accompanied the blood–brain barrier dysfunction in several neurological disorders, especially in multiple sclerosis. The activity of transcription factor ETS1, which is highly expressed in endothelial cells (ECs) and responded to an inflammatory condition, is suppressed in the central nervous system (CNS) ECs in MS and its animal model experimental autoimmune encephalomyelitis. We identify ETS1 as a central regulator of endothelial-to-mesenchymal transition (EndMT) associated with the compromise of barrier integrity. These phenotypical and functional alterations can further induce high permeability, immune infiltration, and organ fibrosis in multiple sclerosis, thus promoting disease progression. Together, these results demonstrate a functional role of EndMT in blood–brain barrier dysfunction and propose ETS1 as a potential transcriptional switch of EndMT to target the development of multiple sclerosis.

Epstein-Barr virus as a driver of multiple sclerosis

Accumulating evidence implicates Epstein-Barr virus (EBV) as an etiological factor in multiple sclerosis (MS). If EBV is a "driver" that causes antiviral immunity with associated autoimmune components rather than a "trigger" that unleashes self-perpetuating autoimmunity, then elimination of EBV would be a rational therapy for MS.

Environmental risk factors in multiple sclerosis: bridging Mendelian randomization and observational studies.

Multiple sclerosis (MS) is a complex disease with both genetic variants and environmental factors involved in disease susceptibility. The main environmental risk factors associated with MS in observational studies include obesity, vitamin D deficiency, Epstein-Barr virus infection and smoking. As modifying these environmental and lifestyle factors may enable prevention, it is important to pinpoint causal links between these factors and MS. Leveraging genetics through the Mendelian randomization (MR) paradigm is an elegant way to inform prevention strategies in MS. In this review, we summarize MR studies regarding the impact of environmental factors on MS susceptibility, thereby paying attention to quality criteria which will aid readers in interpreting any MR studies. We draw parallels and differences with observational studies and randomized controlled trials and look forward to the challenges that such work presents going forward.