Smoking and Epstein\u2013Barr virus infection in multiple sclerosis development

Background: Little is known about risk factors for neuromyelitis optica (NMO) or transverse myelitis (TM). Objective: The objective of this paper is to evaluate whether established multiple sclerosis (MS) risk factors, including smoking history, a history of infectious mononucleosis (IM), anti-EBNA1 Ab titers and HLA-DR15 are associated with NMO or TM. Methods: We conducted a case-control study among participants in the Accelerated Cure Project for Multiple Sclerosis (ACP) Repository, which includes patients with MS, NMO and TM. Controls include related and unrelated individuals without evidence of demyelinating disease. Analyses included 1237 cases of MS, 98 cases of NMO, 133 cases of TM and 488 healthy controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess the association between smoking, HLA-DR15, anti-EBNA1 Ab titers and a history of IM adjusting for gender, study site and ethnicity. Results: Overall, the association between smoking, IM, HLA-DR15 and anti-EBNA1 Ab titers and odds of MS were as expected and no significant interactions were observed. However, there was little evidence of association between these MS risk factors and odds of NMO or TM. Conclusions: Established MS risk factors do not appear to be associated with susceptibility to TM or NMO and, among MS patients, these risk factors appear to act independently.

Epstein-Barr virus (EBV) infection, history of infectious mononucleosis (IM) and HLA-A and DRB1 have all been proposed as risk factors for multiple sclerosis (MS). Our aim was to analyse possible interactions between antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA1) or EBNA1 fragments, presence of DRB1*15 and absence of A*02. The study population includes newly diagnosed cases and matched controls. Interaction on the additive scale was calculated using attributable proportion due to interaction (AP), which is the proportion of the incidence among individuals exposed to two interacting factors that is attributable to the interaction per se. IM showed association with MS, odds ratio (OR)=1.89 (1.45-2.48% confidence interval (CI)), as did raised EBNA1 IgG OR=1.74 (1.38-2.18 95%CI). All EBNA1 fragment IgGs were associated with MS risk. However, EBNA1 fragment 385-420 IgG levels were more strongly associated to MS than total EBNA1 IgG, OR=3.60 (2.75-4.72 95%CI), and also interacted with both DRB1*15 and absence of A*02, AP 0.60 (0.45-0.76 95%CI) and AP 0.39 (0.18-0.61 95%CI), respectively. The observed interaction between HLA class I and II genotype and reactivity to EBV-related epitopes suggest that the mechanism through which HLA genes influence the risk of MS may, at least in part, involve the immune control of EBV infection.

The association between infectious mononucleosis (IM) and risk of breast cancer is unclear; no prospective studies have examined this relationship. We examined self-reported history and age at IM in relation to risk of invasive breast cancer. Self-reported history and age at IM were examined in relation to risk of invasive breast cancer in a large cohort of women, the Nurses' Health Study II (81,807 women followed from 1989 to 2007). Through questionnaires, women were asked whether they ever had IM and if so, at what age. During follow-up, 2,349 cases of invasive breast cancer were documented. Cox proportional hazards regression was used to estimate relative risks (RR) and 95 % confidence intervals (CI) for the association of IM with breast cancer. The multivariable-adjusted RR for history of IM and risk of invasive breast cancer was 1.00 (95 % CI: 0.90-1.11). Similar null results were obtained when estrogen receptor/progesterone receptor positive and negative tumors were considered separately. There were no clear patterns of association between age at IM and risk of breast cancer: compared to women with no history of IM, those who were ≤15 years old when they had IM were at lower risk (RR: 0.77; 95 % CI: 0.60, 0.97), but there was no association for women who had IM at ages 16-19, 20-24, or 30+. However, an increased RR (1.45; 95 % CI: 1.02-2.04) was observed for women who had IM at ages 25-29. Results of this large prospective study do not support a clear association between history of clinical IM and risk of invasive breast cancer.

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...

ObjectiveWe aimed to study (1) to what extent the influence of low sun exposure on multiple sclerosis (MS) risk is mediated by low vitamin D levels; (2) whether low sun exposure or vitamin D deficiency act synergistically with HLA-DRB1*15:01 and absence of HLA-A*02:01.MethodsWe used two population-based case–control studies (7069 cases, 6632 matched controls). Subjects with different HLA alleles, sun exposure habits and vitamin D status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Mediation analysis was used to identify the potential mediation effect of vitamin D on the relationship between low sun exposure and MS risk.ResultsLow sun exposure increased MS risk directly as well as indirectly, by affecting vitamin D status. The direct effect, expressed as OR, was 1.26 (95% CI 1.04–1.45) and the indirect effect, mediated by vitamin D deficiency, was 1.10 (95% CI 1.02–1.23). Of the total effect, nearly 30% was mediated by vitamin D deficiency. There was a significant interaction between low sun exposure and vitamin D deficiency (attributable proportion due to interaction 0.3, 95% CI 0.04–0.5) accounting for about 12% of the total effect. Further, both factors interacted with HLA-DRB1*15:01 to increase MS risk.InterpretationOur findings indicate that low sun exposure acts both directly on MS risk as well as indirectly, by leading to low vitamin D levels. The protective effect of sun exposure thus seems to involve both vitamin D and non-vitamin D pathways, which is of relevance for prevention, in particular for those with a genetic susceptibility to MS.

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.

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.

The link between Epstein–Barr virus (EBV) and multiple sclerosis (MS) has puzzled researchers since it was first discovered over 40 years ago. Until that point, EBV was primarily viewed as a cancer‐causing agent, but the culmination of evidence now shows that EBV has a pivotal role in development of MS. Early MS disease is characterised by episodic neuroinflammation and focal lesions in the central nervous system (CNS) that over time develop into progressive neurodegeneration and disability. Risk of MS is vanishingly low in EBV seronegative individuals, history of infectious mononucleosis (acute symptomatic primary infection with EBV) significantly increases risk and elevated antibody titres directed against EBV antigens are well‐characterised in patients. However, the underlying mechanism – or mechanisms – responsible for this interplay remains to be fully elucidated; how does EBV‐induced immune dysregulation either trigger or drive MS in susceptible individuals? Furthermore, deep understanding of virological and immunological events during primary infection and long‐term persistence in B cells will help to answer the many questions that remain regarding MS pathogenesis. This review discusses the current evidence and mechanisms surrounding EBV and MS, which have important implications for the future of MS therapies and prevention.

BackgroundBenign multiple sclerosis (MS), characterised by minimal disability despite long disease duration, remains poorly understood in terms of its determinants and prognostic implications. While lifestyle factors have been implicated in...

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.

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

ABSTRACTBackgroundEpstein–Barr Virus (EBV) and its clinical manifestation, infectious mononucleosis (IM), are strongly linked to MS risk. A recent in vitro study suggests that HLA‐E*01:03, in contrast to HLA‐E*01:01, may protect against MS through more effective immune responses against EBV‐infected B cells. However, the role of HLA‐E*01 in MS remains unclear.MethodsWe investigated if HLA‐E*01:01 was significantly associated with higher MS risk in individuals with a history of IM diagnosis, using 487,144 individuals from the UK Biobank's cohort. We estimated the interaction between HLA‐E*01:01 and IM using Cox proportional hazard models, adjusting for demographics, smoking, childhood body size, older siblings, and MS‐related HLA alleles (e.g., HLA‐DRB1*15:01).ResultsHLA‐E*01:01 allele alone was not significantly associated with IM or MS (p > 0.05). However, a significant interaction between HLA‐E*01:01 and IM history was observed in relation to MS risk (p < 0.001). Specifically, MS risk was significantly higher in both HLA‐E*01:01 heterozygotes (HR = 1.74 [95% CI: 1.36, 1.97], p < 0.001) and homozygotes (HR = 3.01 [95% CI: 1.81, 3.88], p < 0.001) with IM history, compared to HLA‐E*01:03 homozygotes. Conversely, these associations were non‐significant in individuals without IM history (p > 0.05). The estimated proportion of the combined risk attributable to interaction effects was 40% in HLA‐E*01:01 heterozygotes and 65% in HLA‐E*01:01 homozygotes.ConclusionsHLA‐E*01:01 carriers diagnosed with IM are at significantly increased risk of MS, independently from other MS‐related HLA alleles. This supports the hypothesis that HLA‐E*01:01 may contribute to MS susceptibility due to weaker immune control over EBV infection. Incorporating HLA‐E*01:01 into existing MHC‐based MS risk models could then enhance personalized risk assessments in individuals with IM history.

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.

In a recent review evaluating the evidence concerning the association between smoking and multiple sclerosis (MS), the author specifically calls for: (1) studies investigating this association using objective markers for smoking in prospective datasets; and (2) studies addressing the timing of smoke exposure [Wingerchuk, 2012]. We have recently reported the findings of a nested case-control study where levels of cotinine, a recognized biomarker for tobacco use, were measured in biobank blood samples collected median 9 years prior to disease onset [Salzer et al. 2012a]. Elevated levels of cotinine suggestive of smoking (≥10 ng/ml) [Vineis et al. 2005] were associated with a 50% increased risk of MS when analyzing the entire cohort. When we stratified the cohort according to age at blood sampling, it was evident that it was only among young subjects (below median age at blood sampling, <26.4 years) that this effect was seen. In addition, we used samples collected in the first trimester from 37 pregnant women, whose offspring had later developed MS, and 185 pregnant women whose offspring had not (further described by Salzer and colleagues [Salzer et al. 2012b]) to study the effects of gestational levels of cotinine on the risk of MS in the offspring (previously unpublished data). In this dataset n = 13 (35%) of case mothers and n = 71 (39%) of control mothers had cotinine levels ≥10 ng/ml. There was no association between elevated cotinine levels during gestation and the risk of MS in the offspring (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.41–1.8, matched logistic regression). In conclusion, our data indicate that smoke exposure during young adulthood is associated with an increased MS risk, but exposure during early gestation according to our limited gestational material, or exposure after the age of 26.4 years is not. This age-of-exposure-dependent effect of smoking on MS risk converges with similar findings for other risk factors of MS (vitamin D levels, elevated body mass index [BMI], Epstein–Barr virus [EBV] seroconversion, infectious mononucleosis) suggesting that young adulthood is a crucial time for establishing an individual’s risk of the disease [Hedstrom et al. 2012; Munger et al. 2006; Thacker et al. 2006].

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.