Low sun exposure increases multiple sclerosis risk both directly and indirectly

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.

BackgroundPrevious studies on the influence of exposure to organic solvents on multiple sclerosis (MS) risk have yielded inconclusive results. AimTo investigate the relationship between exposure to organic solvents and MS...

Multiple sclerosis (MS) is an immune-mediated disorder of central nervous system. It most frequently occurs in young female adults, and the prevalence increases with latitude. So far, over 200 genes, loci and single nucleotide polymorphisms (SNPs) have been linked with MS, although each one contributing only slightly in the overall etiology of the disease. The HLA-DRB1*15:01 haplotype has been shown to have the strongest association with MS occurrence risk in genome-wide association studies (GWAS), while HLA-A*02 has been shown to have a protective effect. The exact etiology of MS is still unclear, but there seems to exist an interplay between genetic burden of an individual, and environmental factors which contribute to MS occurrence such as Epstein-Barr virus (EBV) infection, vitamin D levels, smoking status, and early life obesity. An interaction between HLA-DRB1*15:01 and EBV infection, the strongest environmental risk factor for MS, has been observed. It has been suggested that this interaction is a result of HLA-DRB1*15:01 acting as a coreceptor for EBV, thus providing a pathophysiological explanation connecting environmental with genetic MS risk factors. A recent study including participants from two case-control studies with over 13.000 individuals showed that an interaction exists between sun exposure, vitamin D levels, and HLA-DRB*15:01 carrier status, leading to increased risk of MS in individuals with lower sun exposure, vitamin D deficient, and HLA-DRB*15:01 positive. The interaction of HLA-DRB1*15:01 with smoking has been observed in a meta-analysis, while the same study only showed an interaction of smoking with the absence of HLA-A*02 in a subset of studies. The risk of MS has been shown to vary in obese individuals, with obese individuals with the susceptible genotype (HLA-DRB1*15:01+, HLA-A*02-) having 16x higher odds of having MS compared with non-obese persons with a non-susceptible genotype. 

It is unclear whether smoking interacts with different aspects of Epstein–Barr virus (EBV) infection with regard to multiple sclerosis (MS) risk. We aimed to investigate whether smoking acts synergistically with elevated EBNA-1 antibody levels or infectious mononucleosis (IM) history regarding MS risk. Two Swedish population-based case–control studies were used (6,340 cases and 6,219 matched controls). Subjects with different smoking, EBNA-1 and IM status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). Current and past smokers had higher EBNA-1 antibody levels than never smokers (p < 0.0001). There was an additive interaction between current smoking and high EBNA-1 antibody levels (AP 0.3, 95% CI 0.2–0.4), but not between past smoking and high EBNA-1 antibody levels (AP 0.01, 95% CI − 0.1 to 0.1), with regard to MS risk. An interaction also occurred between current smoking and IM history (AP 0.2, 95% CI 0.004–0.4), but not between past smoking and IM history (AP − 0.06, 95% CI − 0.4 to 0.3). Current smoking increases EBNA-1 antibody levels and acts synergistically with both aspects of EBV infection to increase MS risk, indicating that there is at least one pathway to disease in which both risk factors are involved.

Purpose: Polymorphisms in the genes encoding interleukin-23 receptor (IL23R) and the p40 subunit of IL-12/23 (IL12B) have been implicated in multiple sclerosis (MS) risk. However, results of different studies are inconsistent. Our aim was to perform a meta-analysis on this topic. Methods: We assessed two variants (rs10889677 and rs7517847) of IL23R and the A1188C polymorphism (rs3212227) of IL12B. Electronic databases (PubMed, Web of Science and Scopus) were searched for eligible studies published until September 2014. Odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of association in dominant, recessive, homozygote and allelic comparison models. Results: Seven case–control studies with 2250 MS patients and 2320 controls were included in this meta-analysis. The pooled results showed no association of rs10889677 and rs7517847 with MS risk in any of the genetic models. Although the pooled analysis showed an association between rs3212227 and MS in all study subjects in dominant (OR = 0.81, 95% CI: 0.66–0.99, Ph = 0.480, Pz = 0.044) and allelic comparison (OR = 0.84, 95% CI: 0.72–0.98, Ph = 0.967, Pz = 0.030) models, subgroup analysis based on ethnicity did not suggest an association between rs3212227 and MS risk in Caucasians in any of the genetic models, and there was no association between rs3212227 and MS risk in an Asian group. Conclusions: The IL23R polymorphisms rs10889677, rs7517847, and the IL12B polymorphism rs3212227 are not associated with MS risk.

Both insufficient exposure to sunlight and vitamin D deficiency have been associated with an increased risk for multiple sclerosis (MS). An interaction between human leukocyte antigen HLA-DRB1*15 and vitamin D in MS was recently proposed. We investigated the association between previous exposure to ultraviolet radiation (UVR), vitamin D status at inclusion in the study, and MS risk including the interaction of these factors with HLA-DRB1*15. A population-based case-control study involving 1013 incident cases of MS and 1194 controls was performed in Sweden during 2005-2010. Subjects were classified according to their UVR exposure habits, vitamin D status, and HLA genotypes. The associations between different sun exposure habits/vitamin D levels and MS were calculated as odds ratios (OR) with 95% confidence intervals (CI) using logistic regression. Potential interaction was evaluated by calculating the attributable proportion due to interaction. Subjects with low UVR exposure had a significantly increased risk of MS compared with those who reported the highest exposure (OR 2.2, 95% CI 1.5-3.3). Similarly, subjects who had 25-hydroxy-vitamin D levels less than 50 nM/l had an increased risk for MS (OR 1.4, 95% CI 1.2-1.7). The association between UVR exposure and MS risk persisted after adjustment for vitamin D status. There was no interaction with HLA-DRB1*15 carriage. UVR and vitamin D seem to affect MS risk in adults independently of HLA-DRB1*15 status. UVR exposure may also exert a protective effect against developing MS via other pathways than those involving vitamin D.

To examine the interplay between smoking, serum antibody titers to the Epstein-Barr virus nuclear antigens (anti-EBNA), and HLA-DR15 on multiple sclerosis (MS) risk. Individual and pooled analyses were conducted among 442 cases and 865 controls from 3 MS case-control studies-a nested case-control study in the Nurses' Health Study/Nurses' Health Study II, the Tasmanian MS Study, and a Swedish MS Study. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for the association between smoking, anti-EBNA titers, HLA-DR15, and MS risk. Study estimates were pooled using inverse variance weights to determine a combined effect and p value. Among MS cases, anti-EBNA titers were significantly higher in ever smokers compared to never smokers. The increased risk of MS associated with high anti-EBNA Ab titers was stronger among ever smokers (OR = 3.9, 95% CI = 2.7-5.7) compared to never smokers (OR = 1.8, 95% CI = 1.4-2.3; p for interaction = 0.001). The increased risk of MS associated with a history of smoking was no longer evident after adjustment for anti-EBNA Ab titers. No modification or confounding by HLA-DR15 was observed. The increased risk of MS associated with ever smoking was only observed among those who had high anti-EBNA titers (OR = 1.7, 95% CI = 1.1-2.6). Smoking appears to enhance the association between high anti-EBNA titer and increased multiple sclerosis (MS) risk. The association between HLA-DR15 and MS risk is independent of smoking. Further work is necessary to elucidate possible biologic mechanisms to explain this finding.

Association between IL7 Receptor Alpha (Il7ra) gene rs6897932 polymorphism and the risk of Multiple Sclerosis: A meta-regression and meta-analysis.

Background: HLA-DRB1*15:01, absence of HLA-A*02:01, and smoking interact to increase multiple sclerosis (MS) risk. Objective: To analyze whether MS-associated human leukocyte antigen (HLA) alleles, apart from DRB1*15:01 and absence of A*02:01, interact with smoking in MS development, and to explore whether the established HLA-smoking interaction is affected by the DQA1*01:01 allele, which confers a protective effect only in the presence of DRB1*15:01. Methods: In two Swedish population-based case–control studies (5838 cases, 5412 controls), subjects with different genotypes and smoking habits were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals employing logistic regression. Interaction on the additive scale between different genotypes and smoking was evaluated. Results: The DRB1*08:01 allele interacted with smoking to increase MS risk. The interaction between DRB1*15:01 and both the absence of A*02:01 and smoking was confined to DQA1*01:01 negative subjects, whereas no interactions occurred among DQA1*01:01 positive subjects. Conclusion: Multifaceted interactions take place between different class II alleles and smoking in MS development. The influence of DRB1*15:01 and its interaction with the absence of A*02:01 and smoking is dependent on DQA1*01:01 status which may be due to differences in the responding T-cell repertoires.

This study aimed to quantify the population attributable (or prevented) fraction (PAR or PPF) of common risk factors for multiple sclerosis (MS) including family history of MS and vaccine uptake against influenza A and B viruses and hepatitis B virus. Confirmed MS cases and MS-free controls pair-matched on age (± 5 years), sex and nativity with cases were enrolled. Data were collected through face-to-face interviews both from the cases and controls. An unconditional multivariable logistic regression model was used to analyze the data by including matching factors i.e., age, sex, and nativity as confounders and MS family history and vaccine uptake against influenza viruses and hepatitis B virus as exposures. The adjusted odds ratios and their 95% confidence intervals (CI) were used to compute PAR for family history of MS and PPFs for vaccine uptake against HBV and influenza virus along with their respective 95% CIs. A total of 110 MS cases, and their 110 pair-matched controls were enrolled. The PAF for family history of MS revealed that 22% of MS risk in the population is contributed by family history of MS (PAF = 0.22; 95% CI: 0.10-0.32). The PPFs for vaccination uptake against influenza viruses and/or hepatitis B virus were associated with a significant nonspecific protection against MS risk by 20% (PPF = 0.20; 95% CI: 0.004-0.43) or 30% (PPF = 0.30; 95% CI: 0.03-0.65) respectively. Moreover, the computed joint PPF for vaccination uptake against influenza viruses and hepatitis B virus showed a significantly increased 44% non-specific protection against MS risk (PPF = 0.44; 95% CI: 0.03-0.80). Familial history of MS is associated with 22% population attributable fraction for MS risk, whereas vaccine uptake against influenza viruses or hepatitis B virus conferred a nonspecific protection with population prevented fractions of 20% and 30% respectively suggesting a substantial potential for public health interventions to minimize MS risk in this and other similar settings.

Background: Epistatic interactions between human leukocyte antigen (HLA)-DRB1 alleles alter multiple sclerosis (MS) risk in Caucasians. Such interactions have never been studied in Asian MS patients. Objective: To investigate the influence of HLA-DRB1 alleles, including epistatic interactions at this locus, in Japanese MS patients with and without the anti-aquaporin 4 (AQP4) antibody. Methods: The HLA-DRB1 locus was genotyped in 108 MS patients and 127 healthy controls. MS patients were further classified into two groups according to anti-AQP4 antibody status (27 positive and 81 negative). Results: HLA-DRB1*09 (adjusted odds ratio (OR) = 0.243, 95% confidence interval (CI) 0.099—0.533) and HLA-DRB1*01 (adjusted OR = 0.327, 95% CI 0.103—0.873) decreased the incidence of anti-AQP4 antibody-negative MS. By contrast, HLA-DRB1*12 increased the risk of anti-AQP4 antibody-positive MS (adjusted OR = 3.691, 95% CI 1.233—10.565). Individuals with HLA-DRB1*09/15 decreased the risk of anti-AQP4 antibody-negative MS (adjusted OR = 0.164, 95% CI 0.026—0.593), while those with HLA-DRB1*12/15 increased the risk of anti-AQP4 antibody-positive MS (adjusted OR = 10.870, 95% CI 2.004—81.752). Conclusions: The ability of HLA-DRB1*09 to reduce the risk of anti-AQP4 antibody-negative MS may arise from an interaction with HLA-DRB1*15. By contrast, HLA-DRB1*12 increases susceptibility to anti-AQP4 antibody-positive MS, possibly via an interaction with HLA-DRB1*15.

An inverse association exists between type 2 diabetes mellitus (T2DM) and both plasma vitamin D levels and sun exposure, but vitamin D supplementation does not reduce the incidence. We sought to assess whether there is a dose-dependency in the association between sun exposure and T2DM. The melanoma in Southern Sweden (MISS) cohort is comprised of one thousand women without cancer from age groups between 25 and 64, drawn from the Southern Swedish Population Registry of 1990 by random selection. At the inception of the study, 74% of those women responded in writing to an inquiry (n=29,518) and provided detailed information on their sun exposure habits, age, exercise, education, and age at menarche. At the 11-year follow-up, 24,098 responses were received. We analyzed the data using logistic regression analysis with T2DM as a dependent variable and other as independent. We found a dose-dependent inverse relationship between degree of sun exposure and incidence of T2DM. Compared to women with the greatest sun exposure habits, those with moderate and low sun exposure had an odds ratio (OR) of 1.47, [95% confidence interval (CI)=1.2-1.8] and 2.47, (95% CI=1.8-3.4) for T2DM, respectively. In addition, the OR for T2DM was higher in women with normal BMI than in overweight women [3.72 (95% CI=1.8-7.9) vs. 1.90, (95% CI=1.3-2.7)]. A strong inverse dose-dependent association between sun exposure and T2DM indicated that an inverse causal relationship may exist between sun exposure and the incidence of T2DM, possibly via nitric oxide.

BackgroundThere is no consensus on the vitamin D levels and inflammatory bowel disease (IBD).AimTo conduct a systematic review and meta-analysis to analyze the relationship between IBD and 25(OH)D, sun exposure, and latitude, and to determine whether vitamin D deficiency affects the severity of IBD.MethodsWe searched the PubMed, EBSCO, and ClinicalTrials.gov databases to identify all studies that assessed the association between 25(OH)D, sun exposure, latitude, and IBD through November 1, 2014, without language restrictions. Studies that compared 25(OH)D levels between IBD patients and controls were selected for inclusion in the meta-analysis. We calculated pooled standardized mean differences (SMDs) and odds ratios (ORs).ResultsThirteen case-control studies investigating CD and 25(OH)D levels were included, and eight studies part of above studies also investigated the relationship between UC and 25(OH)D. Both CD patients (SMD: 0.26 nmol/L, 95% confidence interval [CI]: 0.09–0.42 nmol/L) and UC patients (SMD: 0.5 nmol/L, 95% CI: 0.15–0.85 nmol/L) had lower levels of 25(OH)D than controls. In addition, CD patients and UC patients were 1.95 times (OR, 1.95; 95% CI, 1.48–2.57) and 2.02 times (OR, 2.02; 95% CI, 1.13–3.60) more likely to be 25(OH)D deficient than controls. We also included 10 studies investigating the relationship between CD activity and vitamin D. Results showed that patients with active CD (CD Activity Index≥150) were more likely to have low vitamin D levels. In addition, whether low sun exposure and high latitude were related to a high morbidity of CD need to be provided more evidence.ConclusionOur study shows that IBD patients have lower vitamin D levels. For active CD patients, vitamin D levels were low. These findings suggest that vitamin D may play an important role in the development of IBD, although a direct association could not be determined in our study.

To prospectively investigate the association between dietary sodium intake and multiple sclerosis (MS) risk. In this cohort study, we assessed dietary sodium intake by a validated food frequency questionnaire administered every 4 years to 80,920 nurses in the Nurses' Health Study (NHS) (1984-2002) and to 94,511 in the Nurses' Health Study II (NHSII) (1991-2007), and calibrated it using data from a validation study. There were 479 new MS cases during follow-up. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the effect of energy-adjusted dietary sodium on MS risk, adjusting also for age, latitude of residence at age 15, ancestry, body mass index at age 18, supplemental vitamin D intake, cigarette smoking, and total energy intake in each cohort. The results in both cohorts were pooled using fixed effects models. Total dietary intake of sodium at baseline was not associated with MS risk (highest [medians: 3.2 g/d NHS; 3.5 g/d NHSII] vs lowest [medians: 2.5 g/d NHS; 2.8 g/d NHSII] quintile: HRpooled 0.98, 95% CI 0.74-1.30, p for trend = 0.75). Cumulative average sodium intake during follow-up was also not associated with MS risk (highest [medians: 3.3 g/d NHS; 3.4 g/d NHSII] vs lowest [medians: 2.7 g/d NHS; 2.8 g/d NHSII] quintile: HRpooled 1.02, 95% CI 0.76-1.37, p for trend = 0.76). Comparing more extreme sodium intake in deciles yielded similar results (p for trend = 0.95). Our findings suggest that higher dietary sodium intake does not increase the risk of developing MS.

ABSTRACTPurpose: The purpose of this study was to evaluate the association of VDR Apa-I, Bsm-I, Fok-I, Taq-I single nucleotide polymorphisms (SNPs) with multiple sclerosis (MS) risk in an Iranian Kurdish population.Materials and methods: A population including of 118 patients and 124 healthy matched controls were recruited to the study. Genotyping of the SNPs was accomplished using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).Results: The frequency of allele T of Fok-I (P = 0.003) and allele C of Taq-I (P = 0.0003) was significantly different between case and control subjects and showed significant association with risk of MS (OR = 1.84, 95% CI = 1.23–2.76; OR = 1.98, 95% CI = 1.36–2.87, respectively). CT genotype (OR = 1.7, 95% CI = 1.05–2.99) of Fok-I and CC genotype (OR = 2.18, 95% CI = 1.05–4.52) of Taq-I showed a predisposing effect. Combined TT+TC vs. CC for Fok-I (OR = 2.15, 95% = CI 1.29–3.60) and combined CC+TC vs. TT for Taq-I (OR = 2.58, 95% CI 1.51–4.40) were susceptibility genotypes for MS. Apa-I and Bsm-I were not significantly associated with risk of MS (OR < 1, P > 0.05) and any genotypes in any genetic models were not significantly different between cases and controls (P > 0.05).Conclusion: As a result, Fok-I and Taq-I showed significant association with risk of MS, while Apa-I and Bsm-I were not observed to be related to the risk of the disease in this population.