Increased Risk Of Multiple Sclerosis Research Articles

Smoking during pregnancy and risk of multiple sclerosis in offspring and mother: A Danish nationwide register-based cohort study

Background: The association between intra-uterine exposure to maternal smoking and risk of multiple sclerosis (MS) has been little studied and with conflicting results. Objective: To examine the risk of MS in offspring exposed intra-uterine to maternal smoking. In addition, to re-examine prior observations of an elevated risk of MS among smokers, assuming that self-reported smoking during pregnancy reflects the woman’s general smoking habits. Methods: The study cohort included all Danish women, pregnant in the period 1991–2018, (n = 789,299) and singletons from these pregnancies (n = 879,135). Nationwide information on maternal smoking during pregnancy and MS cases in the study cohort were obtained from the Medical Birth Register and the National Patient Register. Cox regression analysis was used to estimate hazard ratios (HRs) for the association between smoking and MS risk. Results: Women who smoked during pregnancy had a 42% increased risk of developing MS compared with non-smoking women (HR = 1.42 (1.32–1.52), n = 1,296). The risk of MS among singletons of women who smoked during pregnancy was 38% higher than that among singletons born to non-smoking women (HR = 1.38 (1.08–1.76), n = 110). Conclusion: Our observations add further to the evidence implicating smoking in the development of MS and suggest that intra-uterine exposure to tobacco smoke may increase MS risk.

Impacts of Air Pollution and Thermal Discomfort in Hospitalizations for Multiple Sclerosis in Sao Paulo, Brazil

Multiple sclerosis (MS) is an autoimmune, neurological, and demyelinating disease of unknown etiology. Neuroinflammation caused by the disease has been associated with air pollution as well as bioclimatic conditions. The aim of this study was to investigate the impacts of air pollution and human thermal discomfort on hospitalizations for multiple sclerosis in Sao Paulo, Brazil, from 2008 to 2015. Generalized Additive Model for Location Scale and Shape (GAMLSS) with Zero Inflated Poisson was used to relate multiple sclerosis hospitalizations in three age groups (less than 30 years old, between 30 and 50 years old, and more than 50 years old) and gender (female and male) with atmospheric pollutants PM10, SO2, NO2, NO, and NOx and thermal discomfort. The results showed that the exposure to an increase of 1 µg/m3 in SO2 concentration is highly associated with a 10% increase of the risk of MS hospitalization (95% CI: 2–21%) in female patients and a 7.5% (95% CI: 1.5–16%) increase in male patients. PM10 and NO were associated with increased MS risk only for female patients, mainly aged between 30 and 50 years old (2% and 1% increase in hospitalizations, respectively). The cold discomfort was also associated with MS hospitalization, mainly in males (2% increase in hospitalizations; 95% IC: 1–3%). These results are important, since there are few studies that relate air pollution and thermal discomfort with hospitalizations for multiple sclerosis in Brazil.

Exploring the Role of Plasma Lipids and Statin Interventions on Multiple Sclerosis Risk and Severity: A Mendelian Randomization Study.

There has been considerable interest in statins because of their pleiotropic effects beyond their lipid-lowering properties. Many of these pleiotropic effects are predominantly ascribed to Rho small guanosine triphosphatases (Rho GTPases) proteins. We aimed to genetically investigate the role of lipids and statin interventions on multiple sclerosis (MS) risk and severity. We used two-sample Mendelian randomization (MR) to investigate (1) the causal role of genetically mimic both cholesterol-dependent (through low-density lipoprotein cholesterol (LDL-C) and cholesterol biosynthesis pathway) and cholesterol-independent (through Rho GTPases) effects of statins on MS risk and MS severity, (2) the causal link between lipids (high-density lipoprotein cholesterol [HDL-C] and triglycerides [TG]) levels and MS risk and severity, and (3) the reverse causation between lipid fractions and MS risk. We used summary statistics from the Global Lipids Genetics Consortium (GLGC), eQTLGen Consortium, and the International MS Genetics Consortium (IMSGC) for lipids, expression quantitative trait loci, and MS, respectively (GLGC: n = 188,577; eQTLGen: n = 31,684; IMSGC (MS risk): n = 41,505; IMSGC (MS severity): n = 7,069). The results of MR using the inverse-variance weighted method show that genetically predicted RAC2, a member of cholesterol-independent pathway (OR 0.86 [95% CI 0.78-0.95], p-value 3.80E-03), is implicated causally in reducing MS risk. We found no evidence for the causal role of LDL-C and the member of cholesterol biosynthesis pathway on MS risk. The MR results also show that lifelong higher HDL-C (OR 1.14 [95% CI 1.04-1.26], p-value 7.94E-03) increases MS risk but TG was not. Furthermore, we found no evidence for the causal role of lipids and genetically mimicked statins on MS severity. There is no evidence of reverse causation between MS risk and lipids. Evidence from this study suggests that RAC2 is a genetic modifier of MS risk. Because RAC2 has been reported to mediate some of the pleiotropic effects of statins, we suggest that statins may reduce MS risk through a cholesterol-independent pathway (that is, RAC2-related mechanism(s)). MR analyses also support a causal effect of HDL-C on MS risk.

The CYP24A1 gene variant rs2762943 is associated with low serum 1,25-dihydroxyvitamin D levels in multiple sclerosis patients.

Vitamin D is considered to play a role in multiple sclerosis (MS) etiopathogenesis. A polymorphism in the CYP24A1 gene, rs2762943, was recently identified that was associated with an increased MS risk. CYP24A1 encodes a protein involved in the catabolism of the active form of vitamin D. The immunological effects of carrying the rs2762943 risk allele were investigated, as well as its role as genetic modifier. Serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (1,25(OH)2 D) were measured in a cohort of 167 MS patients. In a subgroup of patients, expression levels of major histocompatibility complex class II and co-stimulatory molecules were determined by flow cytometry, and serum levels of pro-inflammatory (interferon gamma, granulocyte macrophage colony-stimulating factor, C-X-C motif chemokine ligand 13) and anti-inflammatory (interleukin 10) cytokines and neurofilament light chain were measured by single-molecule array assays. The effect of the rs2762943 polymorphism on disease activity and disability measures was evaluated in 340 MS patients. Compared to non-carriers, carriers of the rs2762943 risk allele were characterized by reduced levels of 1,25(OH)2 D (p = 0.0001) and elevated levels of interferon gamma (p = 0.03) and granulocyte macrophage colony-stimulating factor (p = 0.008), whereas no significant differences were observed for the other markers. The presence of the rs2762943 risk allele had no significant impact on disease activity and disability outcomes during follow-up. However, risk allele carriers were younger at disease onset (p = 0.04). These findings suggest that the CYP24A1 rs2762943 polymorphism plays a more important role in MS susceptibility than in disease prognosis and is associated with lower 1,25(OH)2 D levels and a heightened pro-inflammatory environment in MS patients.

Influence of Body Mass Index on B Lymphocyte Repopulation in Multiple Sclerosis Patients Treated with Anti-CD20 Therapy (P7-3.016)

<h3>Objective:</h3> Investigate an association with BMI and early B cell repopulation in a large cohort of multiple sclerosis (MS) patients treated with CD20-depleting therapy <h3>Background:</h3> Findings from a prior retrospective cohort of 45 patients indicated larger body surface area (BSA) was associated with faster repopulation of B cells after CD20 depletion, attributed to underestimation of CD20-depleting therapy dosing for patients with high BSA. Body mass index (BMI) is also associated with increased MS risk and radiographic markers of disease in relapsing-remitting disease. We aimed to confirm an association with BMI and early B cell repopulation after CD20 depletion therapy in an approximately 4-fold larger sample of patients than prior data. <h3>Design/Methods:</h3> This is a retrospective cohort study at a single academic referral center. Patients were identified through chart review using ICD billing codes. Normal BMI was defined 18.5–25. Overweight/obese BMI was defined as 25 or greater. The outcome of interest was early B cell repopulation defined as presence of greater than or equal to 1% CD19 cells on serum lymphocyte subset profile. Logistic regression was used to compare the categorical outcome on the normal vs overweight/obese BMI groups. <h3>Results:</h3> An initial 405 patients were identified. After excluding patients with missing ocrelizumab infusion and lymphocyte subset data, a total sample size of 157 patients were analyzed. The mean age and female sex of the cohort were 51.8 years (SD 12.9) and 99 (63.1%), respectively. 67 (42.7%) patients were categorized having normal BMI (18.5–25) and 90 (57.3%) patients as overweight/obese BMI (&gt;25). The model revealed an effect of BMI: patients who were overweight/obese showed an increase in repopulation [Coef=0.49, SE=0.22, p=0.03]. There was no effect of sex or age. <h3>Conclusions:</h3> Our study provides supportive evidence that greater BMI is associated with B cell repopulation after CD20-depleting therapy. <b>Disclosure:</b> An immediate family member of Dr. Loeffler has received research support from National Science Foundation. The institution of an immediate family member of Dr. Loeffler has received research support from Amazon. Dr. Han has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Han has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arena Pharmaceuticals.

Myelin Basic Protein Fragmentation by Engineered Human Proteasomes with Different Catalytic Phenotypes Revealed Direct Peptide Ligands of MS-Associated and Protective HLA Class I Molecules.

Proteasomes exist in mammalian cells in multiple combinatorial variants due to the diverse regulatory particles and exchange of catalytic subunits. Here, using biotin carboxyl carrier domain of transcarboxylase from Propionibacterium shermanii fused with different proteasome subunits of catalytic and regulatory particles, we report comprehensive characterization of highly homogenous one-step purified human constitutive and immune 20S and 26S/30S proteasomes. Hydrolysis of a multiple sclerosis (MS) autoantigen, myelin basic protein (MBP), by engineered human proteasomes with different catalytic phenotypes, revealed that peptides which may be directly loaded on the HLA class I molecules are produced mainly by immunoproteasomes. We detected at least five MBP immunodominant core regions, namely, LPRHRDTGIL, SLPQKSHGR, QDENPVVHFF, KGRGLSLSRF and GYGGRASDY. All peptides, except QDENPVVHFF, which originates from the encephalitogenic MBP part, were associated with HLA I alleles considered to increase MS risk. Prediction of the affinity of HLA class I to this peptide demonstrated that MS-protective HLA-A*44 and -B*35 molecules are high-affinity binders, whereas MS-associated HLA-A*23, -A*24, -A*26 and -B*51 molecules tend to have moderate to low affinity. The HLA-A*44 molecules may bind QDENPVVHFF and its deamidated form in several registers with unprecedently high affinity, probably linking its distinct protective phenotype with thymic depletion of the repertoire of autoreactive cytotoxic T cells or induction of CD8+ regulatory T cells, specific to the encephalitogenic MBP peptide.

Multiple sclerosis in the Republic of Bashkortostan: population-specific genetic predictors and the results of a 20-year clinical follow-up study

Identification of a complex of genetic predictors of multiple sclerosis (MS) based on previously obtained results in genome-wide association studies of disease markers (GWAS markers) in a population of MS patients and healthy individuals of the Republic of Bashkortostan (Russian Federation) using polygenic detection. The total study group consisted of 2048 people (641 patients with MS and 1407 healthy individuals) who permanently resided in the Republic of Bashkortostan and belonged to the Bashkir (n=325), Russian (n=772) or Tatar (n=951) nationalities. The analysis of association between MS and polymorphisms previously associated with the disease according to GWAS data was performed. Of the 641 MS patients, 247 were the subject of a 20-year prospective clinical follow-up. The C6orf10 rs3129934*T allele was most significantly associated with MS in Russians (OR=2.00, P=5.85·10-5) and Tatars (OR=2.38, P=8.61·10-7). An increased MS risk in Russians was also associated with the EOMES rs11129295*T (OR=1.56, P=0.007) and IL7R rs1494558*I (OR=1.61, P=0.003) alleles. Meta-analysis confirmed the association of the C6orf10 rs3129934*T, EOMES rs11129295*T and IL7R rs1494558*I alleles with MS in the total group, as well as revealed associations of the INAVA rs7522462*G, IL7R rs10624573*I, CD6 rs17824933*G, GPC5 rs9523762*A and GPR65 rs2119704*C alleles with the disease. Using polygenic analysis, we identified a complex predictor C6orf10 rs3129934*C + INAVA rs7522462*G + CD6 rs17824933*C with a pronounced protective effect against MS in the total group (OR=0.34, PFDR=2.65·10-7). We reproduced the association of eight polymorphisms (C6orf10 rs3129934, INAVA rs7522462, IL7R rs10624573, EOMES rs11129295, GPR65 rs2119704, GPC5 rs9523762, CD6 rs17824933 and CD58 rs2300747) with MS, previously identified in GWAS in European populations. Whole exome or genome sequencing may help to reveal the mechanisms underlying the pathogenesis of MS in populations of the Russian Federation.

MiR-181a-5p is a potential candidate epigenetic biomarker in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal degeneration. Abnormal expression of microRNAs (miRNAs) plays an important role in MS pathology. In this cohort study, differential expression of the four miRNAs (hsa-miR-155-5p,hsa-miR-9-5p,hsa-miR-181a-5p, and hsa-miR-125b-5p) was investigated in 69 individuals, including 39 MS patients (relapsing-remitting MS (RRMS), n=27; secondary progressive MS (SPMS), n=12) and 30 healthy controls. In silico analyses revealed possible genes and pathways specific to miRNAs. Peripheral blood miRNA expressions were detected by quantitative real-time PCR (qPCR). hsa-miR-181a-5p was downregulated and associated with increased MS risk (P=0.012). The other three miRNAs were upregulated and not associated with MS (P<0.05). The area under the curve (AUC) is 0.779. In silico analyses showed that hsa-miR-181a-5p may participate in MS pathology by targeting MAP2K1,CREB1,ATXN1, and ATXN3 genes in inflammation and neurodegeneration pathways. The circulatory hsa-miR-181a-5p can regulate target genes, reversing the mechanisms involved in MS pathologies such as protein uptake and processing, cell proliferation and survival, inflammation, and neurodegeneration. Thus, this miRNA could be used as an epigenomic-guided diagnostic tool and for therapeutic purpose.

Age-specific effects of childhood body mass index on multiple sclerosis risk

ObjectiveHigher body mass index (BMI) during early life is thought to be a causal risk factor for multiple sclerosis (MS). We used longitudinal Mendelian randomisation (MR) to determine whether there is a critical window during which BMI influences MS risk.MethodsSummary statistics for childhood BMI (n ~ 28,000 children) and for MS susceptibility were obtained from recent large genome-wide association studies (GWAS) (n = 14,802 MS, 26,703 controls). We generated exposure instruments for BMI during four non-overlapping age epochs (< 3 months, 3 months–1.5 years, 2–5 years, and 7–8 years) and performed MR using the inverse variance weighted method with standard sensitivity analyses. Multivariable MR was used to account for effects mediated via later-life BMI.ResultsFor all age epochs other than birth, genetically determined higher BMI was associated with an increased liability to MS: Birth [Odds Ratio (OR) 0.81, 95% Confidence Interval (CI) 0.50–1.31, Number of Single-Nucleotide Polymorphisms (NSNPs) = 7, p = 0.39], Infancy (OR 1.18, 95% CI 1.04–1.33, NSNPs = 18, p = 0.01), Early childhood (OR 1.31, 95% CI 1.03–1.66, NSNPs = 4, p = 0.03), Later childhood (OR 1.34, 95% CI 1.08–1.66, NSNPs = 4, p = 0.01). Multivariable MR suggested that these effects may be mediated by effects on adult BMI.ConclusionWe provide evidence using MR that genetically determined higher BMI during early life is associated with increased MS risk. This effect may be driven by shared genetic architecture with later-life BMI.

How does Epstein-Barr virus trigger MS?

Epstein-Barr virus (EBV) is a putative trigger for multiple sclerosis (MS), but clear causality is lacking. In a recent issue of Science, Bjornevik and Cortese etal. utilize longitudinal evaluation of over 10 million adults to demonstrate increased MS risk after EBV infection.

Lack of association between C282Y and H63D polymorphisms in the hemochromatosis gene and risk of multiple sclerosis: A meta-analysis.

Increasing evidence supports the potential role of iron metabolism in multiple sclerosis (MS). Previous studies examining the association between polymorphisms of the hemochromatosis gene (HFE) and susceptibility to MS have yielded inconsistent results. In the present study, a meta-analysis of 7 studies was performed conducted in populations of Caucasian origin using the Comprehensive Meta-analysis 3.0 software. The strength of association between the C282Y and H63D polymorphisms in HFE and MS risk was estimated by odds ratios with 95% confidence intervals. Cochran's Q statistic and I2 tests were applied to quantify heterogeneity between studies. An Egger's test was used to estimate publication bias. The C282Y and H63D polymorphisms had no significant association with increased MS risk (all P≥0.05) in the following genetic comparison models: Dominant model (YY + CY vs. CC or DD + HD vs. HH) and allele contrast (Y vs. C or D vs. H). No apparent publication bias or significant heterogeneity was found between studies. These results suggest that the HFE polymorphisms C282Y and H63D are not associated with susceptibility to MS in populations of Caucasian origin. Further studies should be performed in a larger series of MS patients to evaluate the contribution of HFE and other genetic variants associated with iron regulation in the development and progression of MS.

The increased risk of multiple sclerosis associated with HLA-DRB1*15:01 and smoking is modified by alcohol consumption

Previous studies have observed an inverse association between alcohol consumption and multiple sclerosis (MS) risk. We aimed to investigate possible interactions between alcohol consumption, MS-associated human leukocyte antigen (HLA) genes and smoking regarding MS risk. We used a Swedish population-based case–control study (2059 incident cases, 2887 controls) matched by age, sex, and residential area. Subjects with different genotypes and alcohol consumption habits were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals using logistic regression models. Interaction on the additive scale between non-drinking and both genotype and smoking were assessed by calculating the attributable proportion due to interaction (AP). There was a dose-dependent inverse association between alcohol consumption and MS risk (p for trend < 0.0001). A potentiating effect was observed between non-drinking and presence of DRB1*15:01 (AP 0.3, 95% CI 0.2–0.5) which was of similar magnitude irrespective of smoking habits. Non-drinking also interacted with smoking to increase MS risk (AP 0.2, 95% CI 0.06–0.4). Non-drinking interacts with DRB1*15:01 and smoking to increase the risk of MS. Better understanding of the mechanisms behind our findings may help to define ways to achieve protection against MS by other means than alcohol consumption.

Association of Body Mass Index in Adolescence and Young Adulthood and Long-term Risk of Multiple Sclerosis: A Population-Based Study.

To prospectively investigate the long-term relationship between body mass index (BMI) in adolescents and young adults and risk for multiple sclerosis (MS) at the population level. We used data from the population-based compulsory Norwegian tuberculosis screening program during 1963 to 1975, including objectively measured height and weight from ≈85% of all eligible citizens. This was combined with data from the Norwegian MS registry and biobank up to November 2020. BMI was standardized according to age and sex, and risk for MS was calculated with Cox proportional hazard models. During 30,829,506 years of follow-up, we found 1,409 cases of MS among 648,734 participants in eligible age groups (14-34 years). Overall, obesity was associated with increased MS risk (hazard ratio [HR] 1.53 [95% confidence interval (CI) 1.25-1.88]), and the risk was similar in men (HR 1.4 [95% CI 0.95-2.06] and women (HR 1.59 [95% CI 1.25-2.02]). Risk was highest for the youngest age groups (age 14-16: HR 1.73 [95% CI 1.19-2.53]; 17-19: HR 1.61 [95% CI 1.08-2.39]; 20-24: HR 1.56 [95% CI 1.04-2.36]) and was no longer present for those >30 years of age. High BMI in individuals 14 to 24 years of age was associated with increased MS risk later in life in both male and female individuals.

Kissing genetic MS risk loci to life.

Multiple sclerosis (MS) is an inflammatory autoimmune demyelinating disease of the central nervous system (CNS) [1]. Its debilitating effects on sensory, motor, autonomic, and neurocognitive functions affect primarily young adults, especially women (two to three times more frequent than in men), and is most frequent in northern countries, affecting more than 150 individuals of every 100,000 inhabitants e.g. in Canada and the Scandinavian countries. The development of this often initially relapsing/remitting and later progressive disease is associated with genetic and environmental risk factors [1, 3]. The major histocompatibility complex (MHC) class II gene locus is by far the most prominent genetic risk factor, and altered immune responses to the Epstein Barr virus (EBV), the causative infectious agent of most cases of infectious mononucleosis or “kissing disease”, have in recent years emerged as the most prominent environment induced risk factors for MS [1]. Interestingly, particularly infectious mononucleosis as symptomatic primary EBV infection, caused by a lymphocytosis of mainly lytic EBV antigen specific CD8+ T cells, and elevated antibody responses against EBV have been found to synergize with the MS associated MHC class II molecule HLA-DRB1*1501 to increase MS risk seven- to fifteen-fold, respectively [1]. Moreover, EBV infection seems to precede MS onset by several years in nearly all patients. Thus, EBV infection currently appears as a prerequisite for MS development that increases the risk for this autoimmune disease in genetically susceptible individuals.

Low sun exposure acts synergistically with high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels in multiple sclerosis etiology.

Among multiple sclerosis (MS) patients, an association has been observed between low levels of vitamin D and high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels. However, whether sun exposure/vitamin D moderates the role of Epstein-Barr virus (EBV) infection in MS etiology is unclear. We aimed to investigate potential synergistic effects between low sun exposure and elevated EBNA-1 antibody levels regarding MS risk. We used a population-based case-control study involving 2017 incident cases of MS and 2443 matched controls. We used logistic regression models to calculate the odds ratios of MS with 95% confidence intervals (CIs) in subjects with different sun exposure habits and EBNA-1 status. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). Low sun exposure acted synergistically with high EBNA-1 antibody levels (AP 0.2, 95% CI 0.03-0.3) in its association to increased MS risk. The interaction was present regardless of HLA-DRB1*15:01status. Low sun exposure may either directly, or indirectly by affecting vitamin D levels, synergistically reinforce pathogenic mechanisms, such as aspects of the adaptive immune response, related to MS risk conveyed by EBV infection.

High antibody levels against human herpesvirus-6A interact with lifestyle factors in multiple sclerosis development

Background: Infection with human herpesvirus 6A (HHV-6A) has been suggested to increase multiple sclerosis (MS) risk. However, potential interactions between HHV-6A and environmental/lifestyle risk factors for MS have not previously been studied. Methods: We used two Swedish population-based case-control studies comprising 5993 cases and 5995 controls. Using logistic regression models, subjects with different HHV-6A antibody levels, environmental exposures, and lifestyle habits were compared regarding MS risk, by calculating odds ratios (ORs) with 95% confidence intervals (CIs). Potential interactions between high HHV-6A antibody levels and common environmental exposures and lifestyle factors were evaluated on the additive scale. Results: High HHV-6A antibody levels were associated with increased risk of developing MS (OR = 1.5, 95% CI = 1.4–1.6). Regarding MS risk, significant interactions were observed between high HHV-6A antibody levels and both smoking (attributable proportion (AP) = 0.2, 95% CI = 0.1–0.3), low ultraviolet radiation (UVR) exposure (AP = 0.3, 95% CI = 0.1–0.4), and low vitamin D levels (AP = 0.3, 95% CI = 0.0–0.6). Conclusion: High HHV-6A antibody levels are associated with increased MS risk and act synergistically with common environmental/lifestyle risk factors for MS. Further research is needed to investigate potential mechanisms underlying the interactions presented in this study.

Factors affecting the risk of relapsing-onset and progressive-onset multiple sclerosis

ObjectiveIt has been debated whether the different clinical disease courses in multiple sclerosis (MS) are the consequence of different pathogenic mechanisms, with distinct risk factors, or if all MS clinical...

Antibiotic Use and Risk of Multiple Sclerosis: A Nested Case-Control Study in Emilia-Romagna Region, Italy

Introduction: Known risk factors for multiple sclerosis (MS) include smoking, a low vitamin D status, obesity, and EBV, while the inflammatory feature of the disease strongly suggests the presence of additional infectious agents. The association between use of antibiotics and MS risk that could shed light on these factors is still undetermined. We aimed to evaluate the association between antibiotics and MS risk, in the Emilia-Romagna region (RER), Italy. Methods: All adult patients with MS seen at any RER MS center (2015–2017) were eligible. For each of the 877 patients included, clinical information was collected and matched to 5 controls (RER residents) (n = 4,205) based on age, sex, place of residence, and index year. Information on antibiotic prescription was obtained through the linkage with the RER drug prescription database. Results: Exposure to any antibiotic 3 years prior to the index year was associated with an increased MS risk (OR = 1.52; 95% CI = 1.29–1.79). Similar results were found for different classes. No dose-response effect was found. Discussion/Conclusions: Our results suggest an association between the use of antibiotics and MS risk in RER population. However, further epidemiological studies should be done with information on early life and lifestyle factors.

DRB1–environment interactions in multiple sclerosis etiology: results from two Swedish case–control studies

ObjectiveWe aimed to investigate the influence of environmental risk factors for multiple sclerosis (MS) in different genetic contexts, and study if interactions between environmental factors and human leucocyte antigen (HLA)...

The relative contributions of obesity, vitamin D, leptin, and adiponectin to multiple sclerosis risk: A Mendelian randomization mediation analysis

Background: Obesity is associated with increased risk of multiple sclerosis (MS); however, the underlying mechanisms remain unclear. Objective: To determine the extent to which decreased vitamin D bioavailability and altered levels of adiponectin and leptin mediate the association between obesity and MS. Methods: We performed Mendelian randomization (MR) analyses to estimate the effects on MS of body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin, and leptin levels in a cohort of 14,802 MS cases and 26,703 controls. We then estimated the proportion of the effect of obesity on MS explained by these potential mediators. Results: Genetic predisposition to higher BMI was associated with increased MS risk (odds ratio (OR) = 1.33 per standard deviation (SD), 95% confidence interval (CI) = 1.09–1.63), while higher 25OHD levels reduced odds of MS (OR = 0.72 per SD, 95% CI = 0.60–0.87). In contrast, we observed no effect of adiponectin or leptin. In MR mediation analysis, 5.2% of the association between BMI and MS was attributed to obesity lowering 25OHD levels (95% CI = 0.3%–31.0%). Conclusions: This study found that a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no effect. Consequently, vitamin D supplementation would only modestly reverse the effect of obesity on MS.