Ak Hedström

Epstein-Barr virus and multiple sclerosis: interaction with HLA.

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.

Sunlight is associated with decreased multiple sclerosis risk: no interaction with human leukocyte antigen-DRB1*15.

Background:  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.

Smoking is a major preventable risk factor for multiple sclerosis

Background: Both smoking and exposure to passive smoking have repeatedly been associated with increased multiple sclerosis (MS) risk, but have never before been studied together. We assessed the public health impact of these factors. Methods: In a Swedish population-based case-control study (2455 cases, 5336 controls), we calculated odds ratios of developing MS associated with different categories of tobacco smoke exposure, together with 95% confidence intervals, by using logistic regression. The excess proportion of cases attributable to smoking and passive smoking was calculated as a percentage. Results: Both smoking and exposure to passive smoking contribute to MS risk in a dose-dependent manner. At the population level, 20.4% of all cases were attributable to smoke exposure. Among subjects carrying the genetic risk factor HLA-DRB1*15 but lacking HLA-A*02, 41% of the MS cases were attributable to smoking. Conclusions: From a public health perspective, the impact of smoking and passive smoking on MS risk is considerable. Preventive measures in order to reduce tobacco smoke exposure are, therefore, essential. In particular, individuals with a history of MS in the family should be informed regarding the impact of smoking on the risk of MS, and the importance of preventing their children from being exposed to passive smoke.

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.

Body mass index during adolescence, rather than childhood, is critical in determining MS risk

Objective: Obesity in childhood and during adolescence has repeatedly been associated with increased risk of developing multiple sclerosis (MS). We aimed to investigate whether the most critical period occurs during childhood or later, during adolescence. Methods: Using a population-based case-control study (1586 cases and 2800 controls), individuals with different body sizes at age 10 and different body mass indices at age 20 were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals. Potential interactions between HLA-DRB1*15 and absence of HLA-A*02, respectively, and both childhood and adolescent obesity were evaluated by calculating the attributable proportion due to interaction. Results: Regardless of body size at age 10, individuals with adolescent obesity had a 90% increased risk of MS. Among participants who were not obese at age 20, no association was observed between body size at age 10 and subsequent MS risk. An interaction was observed between the HLA MS risk genes and adolescent, but not childhood, obesity. Conclusions: Our results suggest that BMI during adolescence, rather than childhood, is critical in determining MS risk.

Smokers run increased risk of developing anti-natalizumab antibodies:

Background: Smoking may contribute to the induction of neutralizing antibodies to interferon β-1a. Objective: In this study, we aimed to investigate the influence of smoking on the risk of developing antibodies to natalizumab, another biological drug in the treatment of multiple sclerosis. Methods: This report is based on 1338 natalizumab-treated multiple sclerosis patients included in either of two Swedish case-control studies in which information on smoking habits was collected. Using logistic regression, patients with different smoking habits were compared regarding risk of developing anti-natalizumab antibodies, by calculating odds ratios with 95% confidence intervals. Results: Compared with nonsmokers, the odds ratio of developing anti-natalizumab antibodies was 2.4 (95% CI 1.2–4.4) for patients who smoked at the time of screening, and a significant trend showed higher risk of developing antibodies with higher intensity of smoking. When smoking within two years prior to screening was considered, the odds ratio of developing anti-natalizumab antibodies was 2.7 (1.5–5.1). Interpretations: The finding strengthens our hypothesis of the lungs as immune-reactive organs on irritation in relation to autoimmune responses, and may also be of clinical relevance since antibodies against natalizumab abrogate the therapeutic effect of the treatment.

Shift work influences multiple sclerosis risk

Background: An association between working shift at a young age and subsequent risk for multiple sclerosis (MS) has been observed. Objective: To investigate whether this finding could be replicated, and to further explore the influence of age at first exposure to shift work. Methods: Using a Swedish population-based, case-control study (2337 cases and 4904 controls), the incidence of MS among subjects whom had worked shifts was compared with that of those whom had not, by calculating odds ratios (ORs) with 95% confidence intervals (CIs) by means of logistic regression. Results: The OR of developing MS was 1.5 (95% CI 1.2–1.8) among those whom started working shifts before age 20, whereas a less pronounced association was observed among those whom started working shifts at age 20 or later (OR 1.2; 95% CI 1.1–1.4). The effect of shift work was more pronounced among subjects whom had been exposed at a young age, regardless of the duration between the start of shift work and disease onset. Conclusion: Some aspects of adolescence seem to be of great importance, regarding the impact of shift work on MS risk. Circadian disruption and sleep deprivation may contribute towards explaining the association; however, the exact mechanisms behind our observations remain to be elucidated.

Obesity interacts with infectious mononucleosis in risk of multiple sclerosis.

The possible interaction between adolescent obesity and past infectious mononucleosis (IM) was investigated with regard to multiple sclerosis (MS) risk.

Environmental factors and their interactions with risk genotypes in MS susceptibility.

PURPOSE OF REVIEW The area of multiple sclerosis (MS) epidemiology has expanded during the last few years. Established lifestyle and environmental factors influencing MS risk are Epstein-Barr virus infection, sun exposure/vitamin D, and smoking. We review these factors and a series of other potential candidates implicated in the pathogenesis of MS and how environmental factors interact with genetic susceptibility with regard to disease risk. RECENT FINDINGS On top of established MS-associated factors, there is now strong evidence for influence of adolescent obesity, exposure to organic solvents and shift work, all demonstrating increased risk of disease. Other factors, such as nicotine, alcohol, and high coffee consumption are associated with decreased MS risk. A number of lifestyle/environmental factors, including smoking and obesity, seem to interact with MS risk human leukocyte antigen genes, conferring much stronger effects on disease risk among those exposed to both factors. Furthermore, an interaction between two environmental factors, obesity and infectious mononucleosis, with regard to MS risk, has been demonstrated in two independent studies. SUMMARY MS is a complex disease for which both genetic susceptibility and lifestyle/environmental factors are important, and where the latter may be of great importance. Lifestyle and environmental factors can often be modified and may denote pathogenic pathways.

Exposure to anaesthetic agents does not affect multiple sclerosis risk

It has been hypothesized that exposure to anaesthetic agents, some of which are chemically related to organic solvents, may affect the risk of developing multiple sclerosis (MS). The aim of this study was to estimate the influence of occupational exposure to anaesthetic agents on the risk for MS. We further aimed to investigate the impact of general anaesthesia and usage of nitrous oxide.