Risk Factor For Multiple Sclerosis Research Articles

Higher fish consumption and lower risk of central nervous system demyelination.

The evidence for diet as a risk factor for multiple sclerosis (MS) is inconclusive. We examined the associations between fish consumption and risk of a first clinical diagnosis of central nervous system demyelination (FCD), a common precursor to MS. The 2003-2006 Ausimmune Study was a case-control study examining environmental risk factors for FCD, with participants recruited from four regions of Australia and matched on age, sex, and study region. Dietary intake data were collected using a food frequency questionnaire. We used conditional logistic regression models to test associations between fish consumption (total, tinned, grilled, and fried) and risk of FCD (249 cases and 438 controls), adjusting for history of infectious mononucleosis, smoking, serum 25-hydroxyvitamin D concentrations, socio-economic status, omega-3 supplement use, dietary under-reporting, and total energy intake. Higher total fish consumption (per 30 g/day, equivalent to two serves/week) was associated with an 18% reduced risk of FCD (AOR 0.82; 95% CI 0.70, 0.97). While we found no statistically significant associations between grilled and fried fish consumption and risk of FCD, higher tinned fish consumption (per 30 g/day) was associated with a 41% reduced risk of FCD (AOR 0.59; 95% CI 0.39, 0.89). Tinned fish is predominantly oily, whereas grilled and fried fish are likely to be a combination of oily and white types. Oily fish is high in vitamin D and very long chain polyunsaturated omega-3 fatty acids, both of which may be beneficial in relation to MS.

Environmental and genetic risk factors for MS: an integrated review.

Recent findings have provided a molecular basis for the combined contributions of multifaceted risk factors for the onset of multiple sclerosis (MS). MS appears to start as a chronic dysregulation of immune homeostasis resulting from complex interactions between genetic predispositions, infectious exposures, and factors that lead to pro‐inflammatory states, including smoking, obesity, and low sun exposure. This is supported by the discovery of gene–environment (GxE) interactions and epigenetic alterations triggered by environmental exposures in individuals with particular genetic make‐ups. It is notable that several of these pro‐inflammatory factors have not emerged as strong prognostic indicators. Biological processes at play during the relapsing phase of the disease may result from initial inflammatory‐mediated injury, while risk factors for the later phase of MS, which is weighted toward neurodegeneration, are not yet well defined. This integrated review of current evidence guides recommendations for clinical practice and highlights research gaps.

Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk

Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr virus (EBV) infection is a strong suspect. We have previously identified increased autoantibody levels toward the chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity toward ANO2 and EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology in plasma samples from 8,746 MS cases and 7,228 controls. We detected increased anti-ANO2 antibody levels in MS (P = 3.5 × 10-36) with 14.6% of cases and 7.8% of controls being ANO2 seropositive (odds ratio [OR] = 1.6; 95% confidence intervals [95%CI]: 1.5 to 1.8). The MS risk increase in ANO2-seropositive individuals was dramatic when also exposed to 3 known risk factors for MS: HLA-DRB1*15:01 carriage, absence of HLA-A*02:01, and high anti-EBNA1 antibody levels (OR = 24.9; 95%CI: 17.9 to 34.8). Reciprocal blocking experiments with ANO2 and EBNA1 peptides demonstrated antibody cross-reactivity, mapping to ANO2 [aa 140 to 149] and EBNA1 [aa 431 to 440]. HLA gene region was associated with anti-ANO2 antibody levels and HLA-DRB1*04:01 haplotype was negatively associated with ANO2 seropositivity (OR = 0.6; 95%CI: 0.5 to 0.7). Anti-ANO2 antibody levels were not increased in patients from 3 other inflammatory disease cohorts. The HLA influence and the fact that specific IgG production usually needs T cell help provides indirect evidence for a T cell ANO2 autoreactivity in MS. We propose a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of MS.

Vaccination not a risk factor for multiple sclerosis

Vaccination not a risk factor for multiple sclerosis

A large case-control study on vaccination as risk factor for multiple sclerosis

To investigate the hypothesis that vaccination is a risk factor for multiple sclerosis (MS) by use of German ambulatory claims data in a case-control study. Using the ambulatory claims data of the Bavarian Association of Statutory Health Insurance Physicians covering 2005-2017, logistic regression models were used to assess the relation between MS (n = 12,262) and vaccinations in the 5 years before first diagnosis. Participants newly diagnosed with Crohn disease (n = 19,296) or psoriasis (n = 112,292) and participants with no history of these autoimmune diseases (n = 79,185) served as controls. The odds of MS were lower in participants with a recorded vaccination (odds ratio [OR] 0.870, p < 0.001 vs participants without autoimmune disease; OR 0.919, p < 0.001 vs participants with Crohn disease; OR 0.973, p = 0.177 vs participants with psoriasis). Lower odds were most pronounced for vaccinations against influenza and tick-borne encephalitis. These effects were consistently observed for different time frames, control cohorts, and definitions of the MS cohort. Effect sizes increased toward the time of first diagnosis. Results of the present study do not reveal vaccination to be a risk factor for MS. On the contrary, they consistently suggest that vaccination is associated with a lower likelihood of being diagnosed with MS within the next 5 years. Whether this is a protective effect needs to be addressed by future studies.

Integrative analysis revealed potential causal genetic and epigenetic factors for multiple sclerosis.

Many genomic loci have been identified for multiple sclerosis (MS) by genome-wide association studies (GWAS). Discrimination of the most functionally relevant genes in these loci remains challenging. The aim of this study was to highlight potential causal genes for MS. We detected potential causal DNA methylations and gene expressions for MS by integrating data from large scale GWAS and quantitative trait locus (QTL) studies using the summary data-based Mendelian randomization method. Potential functional SNPs in the identified genes were searched. We found 178 DNA methylation sites and mRNA expressions of 29 genes that were causally associated with MS. The identified genes enriched in 21 specific KEGG pathways and 80 GO terms (e.g., antigen processing and presentation, interferon gamma mediated signaling pathway). Among the identified non-MHC genes, METTL21B, METTL1 and TSFM were strongly connected. MS-associated SNPs in DDR1 were strongly associated with plasma MHC class I polypeptide-related sequence B (MICB) and Granzyme A levels. And plasma MICB and Granzyme A levels were causally associated with MS. Many SNPs in the causal genes showed QTL effects. The association between m6A-SNPs rs923829 and METTL21B expression level was validated in 40 unrelated Chinese Han individuals. This study identified many DNA methylations and genes as important risk factors for MS and provided novel evidence on the association between circulating MICB and Granzyme A and MS. We also showed that the interaction among DDR1, MICB and GZMA and interaction among METTL21B, METTL1 and TSFM may participate in the pathogenesis of MS.

Protective and Risk Factors in Multiple Sclerosis

Several factors are involved in susceptibility to multiple sclerosis (MS)and alterations in disease activity. A full understanding regarding the mechanism which causes the disease is still lacking. Several factors have been considered to be associated, positively or negatively, with the onset, course, progression, and relapse rates of MS. However, the level of consensus on each factor is different. These factors are either genetic (including polymorphisms in human leukocyte antigen, microRNAs genes, etc) or environmental (such as serum levels of circulating vitamin D, helicobacter pylori, Epstein-Barr virus, human cytomegalovirus, human herpes virus type 6, human endogenous retrovirus infections, and latitude). Vitamin D sufficiency is a major protective factor on which there is a decisive consensus and has known interactions with many factors affecting MS onset/severity. Vitamin D therapy is speculated to exert beneficial effects on patients, the efficacy of which, along with the etiology of MS, is reviewed in this article.

Lifestyle-based modifiable risk factors in multiple sclerosis: review of experimental and clinical findings.

Multiple sclerosis (MS) is a lifelong inflammatory and neurodegenerative disease influenced by multiple lifestyle-based factors. We provide a narrative review of the effects of modifiable risk factors that are identified as being associated with risk to develop MS and/or influencing the future clinical disease outcomes. The emerging data regarding the beneficial effects of diet modifications and exercise are further reviewed. In contrast, obesity and comorbid cardiovascular diseases are associated with increased MS susceptibility and worse disease progression. In addition, the potential influence of smoking, coffee and alcohol consumption on MS onset and disability development are discussed. Successful management of the modifiable risk factors may lead to better long-term outcomes and improve patients' quality of life. MS specialists should participate in educating and facilitating lifestyle-based modifications as part of their neurological consults.

Multiple sclerosis among first- and second-generation immigrants in Denmark: a population-based cohort study.

Multiple sclerosis is a disease with a highly variable incidence worldwide. While knowledge about multiple sclerosis risk factors has grown over the years, the aetiology of multiple sclerosis has still not been fully established. We examined multiple sclerosis incidence rates among first-generation immigrants in Denmark, a high-incidence country, and their Danish-born children (second-generation immigrants), to evaluate the importance and timing of exposure to environmental factors in the aetiology of multiple sclerosis. By means of the Danish Civil Registration System we identified 9 121 187 individuals living in Denmark between 1968 and 2015, including 1 176 419 first-generation and 184 282 second-generation immigrants. Study participants were followed for multiple sclerosis in the Danish Multiple Sclerosis Registry from 1968 to 2015. The relative risk (RR) of multiple sclerosis according to immigration status was estimated by means of multiple sclerosis incidence rate ratios obtained in log-linear Poisson regression analysis. Altogether, 16 905 cases of multiple sclerosis were identified in the study cohort, 578 among first-generation and 106 among second-generation immigrants. Multiple sclerosis risk among first-generation immigrants whose parents were born in low, intermediate and high multiple sclerosis risk areas were 21% (RR = 0.21; 95% CI: 0.16-0.28), 43% (RR = 0.43; 95% CI: 0.36-0.50) and 75% (RR = 0.75; 95% CI: 0.67-0.83), respectively, of that among ethnic Danes (test for trend P < 0.0001). First-generation immigrants arriving in Denmark before age 15 years had a multiple sclerosis risk higher than that in their country of birth but lower than that in Denmark, reaching on average 69% of the multiple sclerosis risk among ethnic Danes (RR = 0.69; 95% CI: 0.55-0.87). Multiple sclerosis risk among individuals who came to Denmark at a later age remained closer to that of their country of birth, corresponding to 45% of the multiple sclerosis risk among ethnic Danes (RR = 0.45; 95% CI: 0.41-0.49). Our study supports the idea that environmental factors exerting their role in childhood or adolescence may be of aetiological relevance in multiple sclerosis.

Dietary Modulation of Intestinal Microbiota: Future Opportunities in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease that affects the functioning of the central nervous system (CNS). Recent studies on MS and its animal model, experimental autoimmune encephalomyelitis (EAE), have shown that the composition and abundance of microbes in the intestinal microbiota are an environmental risk factor for the development of MS and EAE. Changes in certain microbial populations in the gastrointestinal tract can cause MS in humans, but MS inflammation can be reduced or even prevented by introducing other commensal microbes that produce beneficial metabolites. Other risk factors for MS include the presence of an altered gut physiology and the interaction between the intestinal microbiota and the immune system. Metabolites including short-chain fatty acids (SCFAs), such as butyrate, are the primary signaling molecules produced by the intestinal microbiota that interact with the host immune system, suggesting an association between MS pathophysiology and gut microbiota. In addition, several host microRNAs present in the gut have been found to interact with the intestinal microbial community, these interactions may indirectly affect the neurological system. Increasing evidence has shown that regulation of the intestinal microbiota is an important approach for reducing MS inflammation. Thus, here we review the use of diet to alter the gut microbiota and its application in the treatment and prevention of MS.

Abstract P206: Multiple Sclerosis Risk Factors Improved With Residential Lifestyle Intervention

Rationale: Previous research suggest that lipids, which are important elements in healthy myelin sheaths, could play a role in multiple sclerosis (MS). This study evaluate the effect on lipids of a medical 18-day lifestyle program. Methods: The program is summarized in the word NEWSTART acronym of (N)utrition (vegan diet), (E)xercise, (W)ater, (S)unshine (proper exposure), (T)emperance (proper use of good things and avoiding harmful things), (A)ir (breathing exercises), (R)est, (T)rust in rational, spiritual, and psychological aspects. Patients were seen by certified physicians, nutritionists, and chaplaincy. They received physician consultations, plant-based diet, massage, hydrotherapy and exercise therapy among other modalities. Results: Out of 2081 patients that completed the program in an 11 year period, n=10 had a diagnosis of MS. Only n=9 of the n=10 patients had complete laboratories. Average age of MS patients was 51 (SD 15), 89% were female. At baseline, the average of cholesterol, triglycerides, HDL, and LDL (listed in the same order) was 196, 141, 59, and 100, with an SD of 47.7, 84.3, 10.1, 35.6, minimum of 126, 68, 50, 75, maximum 276, 304, 70, 141 and median 203, 100, 58, 85. On completion of the 18-day program, the average of cholesterol, triglycerides, HDL, and LDL was 174, 129, 49, and 99, SD was 27.4, 64.3, 18.0, 30.1, minimum 139, 64, 28, 69, maximum 214, 270, 87, 147, median 175, 115, 47, 88, t-test values 2.6, 1.2, -.2, 2.9, significant change? ( Yes(p&lt;.02), Yes(p&lt;.2), No(p&lt;.8), Yes(p&lt;0.1). Conclusions: The program is effective in improving lipids of MS patients. The risk factors cholesterol, triglycerides and LDL responded very well to the intervention. HDL decreased a few point but the change was not significant. Patients seem to benefit from the intervention.

Perfluorinated substances, risk factors for multiple sclerosis and cellular immune activation

Perfluorinated alkylated substances (PFASs) have immunomodulatory effects but the impact on multiple sclerosis (MS) and cellular immune functions is only sparsely described. In the present study, we found lower concentrations of the long chain PFAS perfluorooctane sulfonic acid (PFOS) in MS than in healthy controls (HC). In HC, we did not detect associations between PFOS concentrations and immune phenotypes. Analyzing the impact of known MS risk factors on cellular immune functions, we found that smoking and Epstein–Barr nuclear antigen 1 antibodies were associated with distinct circulating immune cell changes. In summary, current background PFAS exposure is not an important risk factor for MS.

Familial multiple sclerosis in a Brazilian sample: Is HLA-DR15 involved in susceptibility to the disease?

BackgroundThe HLA-DR15 extended haplotype HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 comprises the strongest genetic risk factor for multiple sclerosis (MS). The aim of this work was to investigate whether HLA-DR15 alleles were significantly associated with the susceptibility to MS familial forms (MSf) in an admixed Brazilian population. MethodsAssociation analyses between DR15 and the clinical and demographic variables were made. ResultsWe have genotyped 25 familial cases. The DR15 was detected in 11/25 (44%) of them and in none of controls (P < .00001). DR15 was significantly associated to a foreign ancestor background (P = .029) and later age of onset (P = .018).

Cross-sectional study of smoking exposure: no differential effect on OCT metrics in a cohort of MS patients

BackgroundOptical coherence tomography (OCT) provides quantitative measures of retinal layer thickness. Cigarette smoking is a risk factor for multiple sclerosis (MS) onset and disease severity: its effects on OCT metrics have not been assessed.ObjectiveThe objective of this study was to assess the effect of smoking history on retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform (GCIP) of MS patients by OCT.Methods112 MS patients were recruited from the Brigham and Women’s Hospital. Spectralis OCT scans were acquired to measure GCIP, peripapillary RNFL, and total macular volume. Multivariable linear mixed effects regression model assessed RNFL and GCIP change with fixed effects for smoking history while adjusting for optic neuritis eye status, age, disease duration, sex, baseline EDSS, and disease modifying therapies (DMTs).ResultsSmoking histories were available for 102 patients: 46 (45.10%) had a history of smoking cigarettes and 56 (54.90%) never smoked. No statistically significant differences were found between ever-smokers and never-smokers with respect to GCIP, RNFL, and macular volume.ConclusionOur study shows no significant difference in retinal thickness between ever-smokers and never-smokers. If confirmed, this result suggests mechanistic differences between the retina and other central nervous system (CNS) compartments in response to smoking and should be noted when considering OCT as a surrogate measure of CNS activity.

Review of the novelties presented at the 2018 ECTRIMS Congress: 11th Post-ECTRIMS Meeting (I)

The Post-ECTRIMS Meeting is an emblematic event in Spain which seeks to review and disseminate the main advances in multiple sclerosis presented at the ECTRIMS annual congress. In October 2018, the eleventh Post-ECTRIMS meeting was held in Madrid and was attended by the country's leading experts in multiple sclerosis. As a result of this meeting, we present two articles which outline the most interesting novelties discussed there. This first part includes the latest results obtained regarding the influence of modifiable and non-modifiable risk factors in multiple sclerosis, with emphasis on the progress made in the field of genetics, where the discovery of genes associated with multiple sclerosis has increased exponentially. The complexity of the immune system is addressed and some contributions are made on autoimmunity mechanisms, in which bidirectional relations are observed between immune cells and cells residing in the central nervous system, such as microglial cells and astrocytes. Biomarkers, both in serum and cerebrospinal fluid as well as in imaging, are gaining more and more attention due to their current and, above all, potential role in the diagnosis and prognosis of the disease and in the evaluation of the efficacy of treatments. Finally, the observations made regarding changes in structural and functional connectivity in patients and their relationship with clinical alterations are presented.

Shedding light on the link between early life sun exposure and risk of multiple sclerosis: results from the EnvIMS Study.

Lower levels of sun exposure in childhood have been suggested to be associated with increased risk of multiple sclerosis (MS). In this paper we extend previous work, using two novel analytical strategies. Data collected in the Environmental risk factors In MS (EnvIMS) study, a case-control study with MS cases and population-based controls from Canada, Italy and Norway, were used. Participants reported on sun exposure behaviours for 5-year age intervals from birth; we focused on the first three age intervals (≤15 years). We compared two life course epidemiology conceptual models, the critical period and the accumulation model. We also used latent class analysis to estimate MS risk for different latent sun exposure behaviour groups. The analyses included 2251 cases and 4028 controls. The accumulation model was found to be the best model, which demonstrated a nearly 50% increased risk of MS comparing lowest reported summer sun exposure with highest [risk ratio (RR) = 1.47 (1.24, 1.74)]. The latent sun exposure behaviour group, characterized by low sun exposure during summer and winter and high sun protection use, had the highest risk of MS; a 76% increased risk as compared with the group with high sun exposure and low sun protection use [RR = 1.76 (1.27, 2.46)]. Our analyses provide novel insights into the link between sun exposure and MS. We demonstrate that more time indoors during childhood and early adolescence is linked with MS risk, and that sun protection behaviours in those who spend most time indoors may play a key role in increasing risk.

Environmental factors and a risk for multiple sclerosis in the Altai Territory

Multiple sclerosis (MS) is a chronic dysimmune neurodegenerative disease of the central nervous system, the risk of which depends on genetic and environmental factors. The Altai Territory of the Russian Federation shows an increase in the prevalence of MS from 15.5 cases per 100,000population in 1984 to 56.1 in 2017.Objective: to identify potential environmental risk factors for MS in the Altai Territory.Patients and methods. A one-stage randomized study using the method of analytical epidemiology covered 200patients with MS and 200 volunteers without this condition, the representatives of European ethnicity, who were born and lived in the Altai Territory. The investigators surveyed the patients, analyzed their medical records, and assessed the relationship of the prevalence of MS to the characteristics of the territories of residence.Results and discussion. The prevalence of MS was 1.8 times higher in cities and towns than in villages (p=0.003), in areas with heavy metal (lead and molybdenum) ore deposits, chemical and oil refineries located within a 5-km radius from the place of residence. The risk of MS is unassociated with measles, rubella, chicken pox, mumps, whooping cough, herpes infection, chronic nasopharyngeal bacterial infections, diabetes mellitus, allergic status, and contact with household, agricultural, metal, and medicinal poisons, organic solvents, and oil products.Conclusion.The identified environmental risk factors can serve as a basis for recommendations for the prevention of MS in persons at high genetic risk for this disease.

Integrational analysis of miRNAs data sets as a plausible missing linker between Epstein-Barr virus and vitamin D in relapsing remitting MS patients

Given the multifactorial state of autoimmune complex diseases such as multiple sclerosis (MS), it is not clear if different risk factors act jointly or independently. Despite intensive studies investigating multi aspects of MS risk factors, findings with regards to potential biomarkers that may link these risk factors remained largely inconclusive.System biology or data integration utilizes different validated datasets to extract meaningful information and map the plausible biological pathways and networks. As such, we integrated eight transcriptome datasets to find the differentially expressed miRNAs in peripheral blood (PB) between relapsing remitting MS patients (RRMS) and normal group. After identification the targeted genes of miRNAs, the hub genes were used to construct the underlying protein–protein interaction network and signaling pathways.As results, 9 miRNAs were best exemplified by significant dysregulation including hsa-mir-15a, hsa-mir-484, hsa-mir-30d, hsa-mir-145, hsa-mir-363, has-let-7e, hsa-mir-30a, hsa-let-7b, and hsa-mir-146a. System biology analysis of miRNAs in PB of RRMS patients clearly indicates the involvement of miRNAs in many vital pathways and highlighted the possibility of an association between miRNAs with EBV and vitamin D in MS pathogenesis.Described novel pathways and genes related to miRNAs such as Transient receptor potential channels and Acid sphingomyelinase may provide a potential target for therapeutic approaches although further functional studies are warranted to test these candidates.

Bacteria-Host Interactions in Multiple Sclerosis.

Multiple sclerosis (MS) is caused by a complex interaction of genetic and environmental factors. Numerous causative factors have been identified that play a role in MS, including exposure to bacteria. Mycobacteria, Chlamydia pneumoniae, Helicobacter pylori, and other bacteria have been proposed as risk factors for MS with different mechanisms of action. Conversely, some pathogens may have a protective effect on its etiology. In terms of acquired immunity, molecular mimicry has been hypothesized as the mechanism by which bacterial structures such as DNA, the cell wall, and intracytoplasmic components can activate autoreactive T cells or produce autoantibodies in certain host genetic backgrounds of susceptible individuals. In innate immunity, Toll-like receptors play an essential role in combating invading bacteria, and their activation leads to the release of cytokines or chemokines that mediate effective adaptive immune responses. These receptors may also be involved in central nervous system autoimmunity, and their contribution depends on the infection site and on the pathogen. We have reviewed the current knowledge of the influence of bacteria on MS development, emphasizing the potential mechanisms of action by which bacteria affect MS initiation and/or progression.

Multiple sclerosis risk factors contribute to onset heterogeneity

BackgroundThe phenotypic presentation of multiple sclerosis (MS) may predict long-term outcomes and little is known about factors contributing to heterogeneity at MS onset. Given temporality, it is likely MS risk factors also influence presentation of the disease near onset. MethodsUsing a retrospective cross-sectional study of MS cases, we investigated: age of onset (AOO), number of impaired functional domains (NIFDs), time to second relapse (TT2R), and early relapse activity (ERA). Machine learning variable selection was applied to epidemiologic data for each outcome, followed by multivariable regression models. The models were further adjusted for HLA-DRB1*15:01 carrier status and a MS genetic risk score (GRS). The TT2R and ERA analyses were restricted to relapsing remitting MS cases. ResultsHLA-DRB1*15:01, GRS, and smoking were associated with earlier AOO. Cases who were male, obese, had lower education, or had primary progressive MS were older at onset. For NIFDs, those with relapsing remitting MS and of lower SES had increased NIFDs. Among relapsing remitting cases, those who were older at onset, obese, and had polyfocal presentation had shorter TT2R, while ERA was greater among those younger at onset and who were obese. ConclusionIndividual characteristics including age, genetic profiles, obesity, and smoking status contribute to heterogeneity in disease presentation and modulate early disease course evolution.