Reduced Risk Of Multiple Sclerosis Research Articles

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.

Variation of genes encoding nitric oxide synthases and antioxidant enzymes as potential risks of multiple sclerosis development: a preliminary study

Multiple sclerosis (MS) is a neurodegenerative disease characterized by a variable clinical course and diverse pathophysiology, including nitrative and oxidative stresses as well as inflammation. We aimed to detect the potential association between five selected single-nucleotide polymorphisms (SNPs) in genes encoding nitric oxide synthetases as well as antioxidant enzymes and the development of MS in a Polish population. Genomic DNA was isolated from peripheral blood collected from 142 MS patients and 140 controls. Using Taq-Man® probes, we genotyped the following SNPs: rs1879417 in NOS1, and rs2297518 in NOS2 as well as rs4880 in SOD2, rs7943316 in CAT, rs713041 in GPX4. In the case of rs2297518, the C/C genotype and C allele SNP were associated with an enhanced occurrence of MS, while the C/T, T/T genotypes, and T allele of the same polymorphism reduced this risk. Moreover, the C/C homozygote and C allele of the rs4880 SNP reduced MS risk, while the T allele increased the risk. In addition, the A/T heterozygote of rs7943316 polymorphism was associated with an increased risk of MS occurrence. We also detected that the C/C genotype and C allele of rs713041 decreased the risk of MS, whereas the T/T genotype and T allele increased this risk. In conclusion, the results of our study suggest some links between polymorphic variability in the nitrative/oxidative stress-related genes and the risk of MS development in the Polish population.

Recombinant hepatitis B vaccine uptake and multiple sclerosis risk: A marginal structural modeling approach

BackgroundThere has been an ongoing debate regarding the association between uptake of recombinant vaccine against hepatitis B virus (HBV) and multiple sclerosis (MS) risk. This case-control study tested the hypothesis whether recombinant HBV vaccination status is causally associated with MS risk using targeted maximum likelihood estimation (TMLE) technique. MethodsConfirmed 110 MS cases and age (± 5 years), sex and nativity matched (1:1) 110 controls were enrolled. Data were collected on sociodemographics, environmental factors, history of vaccinations and past morbidities through face-to-face interview both from cases and controls. To estimate the causal parameters including marginal odds ratio (OR), causal relative risk (RR), causal risk difference (RD) and their 95% confidence intervals (CIs), we implemented case-control-weighted TMLE for a matched design that uses data-adaptive flexible stacked ensemble-based machine learning system namely Super Learner. Additionally, population preventable fraction (PPF) of MS risk was computed. ResultsThis study demonstrated a significant nonspecific protective effect of HBV vaccination against MS risk (marginal OR 0.44; 95% CI: 0.19–0.68; p = 0.006; causal RR 0.64, 95% CI: 0.46–0.89; p = 0.004). The significant causal RD showed that among the vaccinated 19% fewer MS cases occurred owing to their HBV vaccination (causal RD -0.19; 95% CI: -0.32 – -0.06; p = 0.014). In the source population, vaccination against HBV led to 17.4% reduced MS risk (PPF = 17.4%; 95% CI: 3.8%, 36.3%). ConclusionThe results suggest a significant nonspecific protective effect of recombinant HBV vaccine against MS risk. Future studies may contemplate to confirm these results.

An exploratory study of diet in childhood and young adulthood and adult-onset multiple sclerosis

There is little evidence on the role of diet in childhood/adolescence and multiple sclerosis (MS) in adulthood. The MS Sunshine Study recruited adults with recent-onset MS (n = 602) and matched controls (n = 653). Of these, 84% provided dietary recall for specific ages between childhood and young adulthood (6–10, 11–15 and 16–20 years). We used logistic regression to test associations between age-specific diet and case-control status. Consumption of fruit (all ages), yoghurt (all ages) and legumes (11–15 years) was associated with lower probability of adult-onset MS (all p < 0.05). These results suggest that healthy dietary habits between childhood and young adulthood may reduce MS risk.

Long-term effects of latitude, ambient temperature, and ultraviolet radiation on the incidence of multiple sclerosis in two cohorts of US women.

Differences in multiple sclerosis (MS) risk by latitude have been observed worldwide; however, the exposures driving these associations are unknown. Ultraviolet radiation (UV) has been explored as a risk factor, and ambient temperature has been correlated with disease progression. However, no study has examined the impact of all three exposures. We examined the association between these exposures and incidence of MS within two nationwide prospective cohorts of women, the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII). Both cohorts were followed with biennial questionnaires to ascertain new diagnoses and risk factors. Time-varying exposures to latitude, cumulative average July temperature (°C), and cumulative average July erythemal UV (mW/m2) were predicted at each participant's biennially updated residential addresses. Using Cox proportional hazards models adjusted for MS risk factors, we calculated hazard ratios (HR) and 95% confidence intervals (CIs) within each cohort and pooled via meta-analyses. In multivariable models, there were suggestions that decreasing latitude (meta-analysis multivariable-adjusted HR = 0.72; 95% CI 0.55, 0.94 for women living <35.73° compared with those ≥42.15°, P-for-trend = 0.007) and increasing cumulative average July temperature (meta-analysis multivariable-adjusted HR = 0.81; 95% CI 0.72, 0.91 for each interquartile range increase [3.91°]) were associated with decreasing risk of MS. There was no evidence of heterogeneity between cohorts. We did not observe consistent associations with cumulative average UV. Our results suggest that adult exposures to decreasing latitude and increasing temperature, but not UV, were associated with reduced MS risk in these two cohorts of women. Studies of MS incidence may want to consider temperature as a risk factor.

Breastfeeding is associated with reduced risk of multiple sclerosis in males, predominantly among HLA-DRB1*15:01 carriers.

BackgroundBreastfeeding as an infant appears protective against later development of some autoimmune diseases, but research into its influence on multiple sclerosis (MS) risk has yielded inconclusive results.ObjectiveWe investigated the possible impact of breastfeeding on MS risk.MethodsWe used two population-based case–control studies comprising 3670 cases and 6737 matched controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between MS and exposure to prolonged breastfeeding (4 months or longer) versus reduced breastfeeding (less than 4 months). A meta-analysis of case–control studies that assessed the impact of breastfeeding on MS risk among women and men was conducted.ResultsProlonged breastfeeding was associated with reduced MS risk among men (OR 0.7, 95% CI 0.5–0.9) but not among women (OR 0.9, 95% CI 0.8–1.1). Among men, a synergistic effect was observed between HLA-DRB1*15:01 carrier status and reduced breastfeeding.ConclusionsFindings from the current study add to accumulating evidence that breastfeeding may be a modifiable protective factor for reducing the risk of MS in offspring. When possible, mothers should be supported to breastfeed their infants; however, the mechanism of a sex-specific biologic effect of breastfeeding on MS risk is unclear.

Environmental Risk Factors for Multiple Sclerosis: A Case-control Study in Kerman, Iran.

Background:Several studies have addressed the environmental risk factors for multiple sclerosis (MS). Concerning contradictory results and change of epidemiologic patterns and the role of environmental factors, in the present study, some risk factors, especially environmental factors, on MS were studied.Materials and Methods:This was a retrospective case-control study conducted among 120 patients with MS and 360 healthy individuals in Kerman, Iran. Inclusion criteria included (1) MS disease, diagnosed by a neurologist according to the McDonald criteria, and (2) tendency to participation in the study. Exclusion criteria included (1) suffering from cognitive disorders; (2) incomplete questionnaire; and (3) continuous migration. Data were collected using a questionnaire consisting of personal information and some environmental factors. Data were analyzed using descriptive and inferential statistics.Results:The results showed that diet was associated with a higher risk of MS with the odds ratio (OR) of 14.46 and 95% confidence interval (CI) of 3.02–69.21 (p < 0.001) for vegetarian and OR of 11.74, 95% CI of 4.66–29.57 (p < 0.001) for animal diets. Similarly, vitamin D supplementation contributed to MS risk (OR: 2.27, 95% CI: 1.32–3.89; p < 0.001). In contrast, history of using cow's milk during infancy resulted in a lower risk of MS (OR: 0.33, 95% CI: 0.20–0.52, p < 0.001).Conclusions:This study suggests that different lifestyles including using cow's milk during infancy and avoiding only vegetarian and animal diets may reduce MS risk in southeastern Iran. More studies are suggested to investigate the controversial finding of the negative effect of vitamin D supplementation in this area.

Epidemiology of Multiple Sclerosis: From Risk Factors to Prevention-An Update.

Although genetic susceptibility explains the clustering of multiple sclerosis (MS) within families and the sharp decline in risk with increasing genetic distance, it cannot fully explain the geographical variations in MS frequency and the changes in risk that occur with migration, which support the action of strong environmental factors. Among these, vitamin D status, obesity in early life, infection with the Epstein-Barr virus, and cigarette smoking are the most consistent environmental predictors of MS risk. The authors review the epidemiological data, critically discuss the evidence for causality of these and other associations, and briefly review the possibility of interventions to reduce MS risk.

Mediterranean diet adherence and risk of multiple sclerosis: a case-control study.

We conducted a hospital-based, case-control study to examine the association between Mediterranean diet (MD) and the risk of multiple sclerosis (MS) in Iran. A total of 70 patients with MS and 142 controls underwent face-to-face interviews in the major neurological clinics of Tehran, Iran. Adherence to a MD was assessed using the 9-unit dietary score, to evaluate the level of conformity of the individual's diet to the Mediterranean dietary pattern. Multivariate logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Higher consumption of fruits (OR=0.28, 95% CI: 0.12-0.63, p-value: 0.002) and vegetables (OR=0.23, 95% CI: 0.10-0.53, p-value: 0.001) were significantly associated with reduced MS risk. In both age adjusted and multivariate adjusted model, the OR of MS decreased significantly in the third as compared to the first tertile of MD score (age adjusted OR: 0.21, 95% CI: 0.06-0.67; p-trend: 0.01, Multivariate adjusted OR: 0.23, 95% CI: 0.06-0.89, p-trend: 0.04). Our study suggests that a high quality diet assessed by MD may decrease the risk of MS.

Environmental factors in multiple sclerosis

Although genetic susceptibility explains the clustering of multiple sclerosis (MS) cases within families, the changes in MS risk that occur with migration can be explained only by changes in the environment. The strongest known risk factor for MS is infection with Epstein–Barr virus (EBV). Compared with uninfected individuals, the hazard of developing MS is approximately 15-fold higher among individuals infected with EBV in childhood and about 30-fold higher among those infected with EBV in adolescence or later in life. Although the mechanisms underlying this association remain unclear, the data provide strong evidence of a causal relation between EBV infection and MS risk. Relevant aspects of MS epidemiology beyond genetics are not explained by EBV involvement, however, implying the involvement of other factors. Modifiable factors for MS risk include smoking and childhood obesity. Increased risk of MS in individuals with vitamin D insufficiency has been proposed to explain the strong latitude gradient in MS prevalence. Results of case–control studies that relied on prevalent MS cases have been mixed, however, and potentially influenced by selection and recall biases. In a recent case–control study of individuals presenting with a first demyelinating episode, higher levels of vitamin D, sun exposure or actinic damage were found to be associated with reduced MS risk. Two longitudinal studies have thus far been completed. In the first, based on assessment of vitamin D intake from diet and supplements, the risk of MS was found to be 30% lower among women in the highest quintile compared with those in the lowest quintile. In the second study, conducted among young adults in the US military, vitamin D status was assessed by averaging multiple season-adjusted measures of 25-hydroxyvitamin D (25[OH]D). During an average of 5 years’ follow-up, MS risk among healthy young adults with serum levels of 25(OH) vitamin D >100 nmol/l was about 60% lower than in individuals of the same age and sex with serum 25(OH) vitamin D levels <100 nmol/l. If confirmed, these findings suggest that a high proportion of MS cases could be effectively prevented by vitamin D supplementation. Furthermore, there is growing evidence that vitamin D insufficiency is a risk factor for conversion from clinically isolated syndrome to MS and for MS progression. Both prevention and treatment trials with vitamin D are needed to confirm these findings and to determine optimal levels of vitamin D.

Reverse causality behind the association between reproductive history and MS

Background: Possible associations between childbearing patterns and multiple sclerosis (MS) risk have been studied for a long time, with conflicting results. We aimed to investigate the influence of reproductive history on MS risk. Methods: Using a Swedish population-based case-control study involving incident cases of MS (1798 cases, 3907 controls), we calculated odds ratios (OR) for MS comparing parents with childless subjects together with 95% confidence intervals (CI) employing logistic regression. Results: Overall, there was an association between having children and reduced MS risk among both sexes. Subjects who had become parents within five years prior to the index year had a substantially reduced risk of developing MS (OR 0.6, 95% CI 0.5–0.8 for women, and OR 0.4, 95% CI 0.3–0.6 for men). No association between having children and MS risk was observed when more than 10 years had passed since the birth of the last child. We found no association between increasing offspring number and MS risk. Conclusions: The observed association between reproductive history and MS risk is restricted to a limited time period preceding the index year, with similar findings in both sexes, which contradicts biologic impact of pregnancy on MS risk and argues in favor of reverse causality, i.e. that fecundity is affected by yet-undiagnosed MS.

The initiation and prevention of multiple sclerosis

Although strong genetic determinants of multiple sclerosis (MS) exist, the findings of migration studies support a role for environmental factors in this disease. Through rigorous epidemiological investigation, Epstein-Barr virus infection, vitamin D nutrition and cigarette smoking have been identified as likely causal factors in MS. In this Review, the strength of this evidence is discussed, as well as the potential biological mechanisms underlying the associations between MS and environmental, lifestyle and dietary factors. Both vitamin D nutrition and cigarette smoking are modifiable; as such, increasing vitamin D levels and smoking avoidance have the potential to substantially reduce MS risk and influence disease progression. Improving our understanding of the environmental factors involved in MS will lead to new and more-effective approaches to prevent this disease.

Genetic predictors of 25-hydroxyvitamin D levels and risk of multiple sclerosis

Risk of multiple sclerosis (MS) decreases with increasing plasma levels of 25-hydroxyvitamin D [25(OH)D]. If this association reflected a protective effect of vitamin D, MS risk should be lower among individuals carrying genetic variants that predict high 25(OH)D levels. The aim of the study was to determine whether individuals with genotypes predicting higher 25(OH)D levels have decreased MS risk. Logistic regression was used to assess the association between single nucleotide polymorphisms (SNPs) associated with 25(OH)D levels and MS risk in 1,655 cases and 6,349 controls. Analyses were further stratified by HLA-DR15 status, assessed by genotyping a single SNP strongly correlated with the HLA DRB1 1501 risk haplotype, and complemented by considering a SNP near CYP27B1. SNPs in GC were predictors of 25(OH)D levels, but not MS risk, in either HLA-DR15 negative or HLA-DR15 positive individuals. In contrast, there was a suggestion of a difference in the effect of a CYP2R1 allele dependent on HLA-DR15 genotype. The 'A' allele of CYP2R1 rs10741657 was associated with increased 25(OH)D levels and a non-significant reduced MS risk among HLA-DR15 negative (OR = 0.89, 95% CI: 0.79, 1.01) that was not apparent in HLA-DR15 positive individuals. The 'C' allele of CYP27B1 rs703842 was inversely associated with MS risk; this association appeared stronger among HLA-DR15 negative (OR = 0.79, 95% CI: 0.69, 0.90) compared to HLA-DR15 positive individuals (OR = 0.91, 95% CI: 0.80, 1.04). This preliminary finding suggests the possibility that the putative beneficial effect of vitamin D on MS risk maybe attenuated in individuals carrying the HLA-DR15 MS risk allele.

Body size and risk of MS in two cohorts of US women

To examine whether obesity during childhood, adolescence, or adulthood is associated with an increased risk of multiple sclerosis (MS). Women in the Nurses' Health Study (n = 121,700) and Nurses' Health Study II (n = 116,671) provided information on weight at age 18 and weight and height at baseline, from which body mass index was derived. Women also selected silhouettes representing their body size at ages 5, 10, and 20. Over the total 40 years of follow-up in both cohorts combined, we confirmed 593 cases of MS. Cox proportional hazards models, adjusting for age, latitude of residence, ethnicity, and cigarette smoking, were used to estimate the rate ratios and 95% confidence intervals (CI). Obesity at age 18 (body mass index > or =30 kg/m(2)) was associated with a greater than twofold increased risk of MS (multivariate relative risk(pooled) = 2.25, 95% CI: 1.50-3.37, p trend <0.001). After adjusting for body size at age 20, having a large body size at ages 5 or 10 was not associated with risk of MS, whereas a large body size at age 20 was associated with a 96% increased risk of MS (95% CI: 1.33-2.89, p trend = 0.009). No significant association was found between adult body mass and MS risk. Obese adolescents have an increased risk of developing multiple sclerosis (MS). Although the mechanisms of this association remain uncertain, this result suggests that prevention of adolescent obesity may contribute to reduced MS risk.

Melanocortin 1 receptor genotype, past environmental sun exposure, and risk of multiple sclerosis

Low past sun exposure, fair skin type, and polymorphisms of the MC1R gene have been associated with multiple sclerosis (MS) risk. We aimed to investigate the interplay between melanocortin 1 receptor gene variants, red hair/fair skin phenotype, and past environmental sun exposure in MS. Population-based case-control study in Tasmania, Australia, involving 136 cases with MS and 272 controls randomly drawn from the community and matched on sex and year of birth. Measures included past sun exposure by calendar and questionnaire, spectrophotometric skin type, and MC1R genotype, with any MC1R Arg151Cys, Arg160Trp, or Asp294His alleles present denoted as red hair color (RHC) variant. The association between RHC variant genotype and MS was more evident for women (odds ratio 2.02 [1.15-3.54]) than for men (odds ratio 0.65 [0.27-1.57]) (difference in effect, p = 0.03). The RHC variant genotype was associated with behavioral sun avoidance. In addition, increasing summer sun exposure at ages 6 through 10 years was associated with reduced MS risk among those with no RHC variant (p = 0.03), but not among those with RHC variant genotype (p = 0.15; difference in effect, p = 0.02). Similar findings were evident for other past sun exposure measures and when the sample was restricted to women only. The interplay between red hair color variant genotype, red hair/fair skin phenotype, and multiple sclerosis (MS) is complex. The modification of past sun exposure by MC1R genotype provides further support that ultraviolet radiation or derivatives such as vitamin D may be causally related to a reduced MS risk.

Epidemiology of Multiple Sclerosis: From Risk Factors to Prevention

Although genetic susceptibility explains the clustering of multiple sclerosis (MS) within families and the sharp decline in risk with increasing genetic distance, it cannot fully explain the geographical variations in MS frequency and the changes in risk that occur with migration, which support the action of strong environmental factors. Among these, vitamin D status, infection with the Epstein-Barr virus, and cigarette smoking are emerging as the most consistent predictors of MS risk. In this article, we review the epidemiological data, critically discuss the evidence for causality of these associations, and briefly discuss the possibility of interventions to reduce MS risk.

1,25‐dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking

Multiple sclerosis (MS) is a complex neurodegenerative disease whose pathogenesis involves genetic and environmental risk factors leading to an aberrant, neuroantigen-specific, CD4+ T cell-mediated autoimmune response. In support of the hypothesis that vitamin D3 may reduce MS risk and severity, we found that vitamin D3 and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) inhibited induction of experimental autoimmune encephalomyelitis (EAE), an MS model. To investigate how 1,25-(OH)2D3 could carry out anti-inflammatory functions, we administered 1,25-(OH)2D3 or a placebo to mice with EAE, and subsequently analyzed clinical disease, chemokines, inducible nitric oxide synthase (iNOS), and recruitment of dye-labeled monocytes. The 1,25-(OH)2D3 treatment significantly reduced clinical EAE severity within 3 days. Sharp declines in chemokines, inducible iNOS, and CD11b+ monocyte recruitment into the central nervous system (CNS) preceded this clinical disease abatement in the 1,25-(OH)2D3-treated animals. The 1,25-(OH)2D3 did not directly and rapidly inhibit chemokine synthesis in vivo or in vitro. Rather, the 1,25-(OH)2D3 rapidly stimulated activated CD4+ T cell apoptosis in the CNS and spleen. Collectively, these results support a model wherein inflammation stimulates a natural anti-inflammatory feedback loop. The activated inflammatory cells produce 1,25-(OH)2D3, and this hormone subsequently enhances the apoptotic death of inflammatory CD4+ T cells, removing the driving force for continued inflammation. In this way, the sunlight-derived hormone could reduce the risk of chronic CNS inflammation and autoimmune-mediated neurodegenerative disease.

Does Childhood Exposure to Sunlight Reduce MS Risk

To address the role of childhood sun exposure on the risk for developing multiple sclerosis (MS), researchers studied 79 pairs of identical twins (each including one affected and one unaffected twin). The twins were retrospectively asked to recall their childhood activities relative to those of their co-twin, using nine measures felt to reflect childhood sun exposure, such as “participating in team sports” and “spending more time outside during spring.” No attempt was made to …

Does Sun Exposure Reduce MS Risk

Recent studies have suggested that ultraviolet light may affect the autoimmune process that is thought to lead to multiple sclerosis (MS). With this