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Environmental risk factors for multiple sclerosis
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Miljöfaktorers betydelse för multipel skleros (Swedish)
Abstract [en]

Background Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. It usually strikes during young adulthood, and 2.5 million individuals are estimated to have the disease worldwide. The causes of MS are not known, but several factors have been shown to be associated with the risk of the disease, including certain genes, vitamin D, smoking and Epstein- Barr virus infection. Little is known about how/if these factors interact.

Methods Study I: The risk of MS by month of birth was investigated using MS cases from the Swedish MS registry and using general population controls. Studies II–V: We identified MS cases who had donated blood prior to disease onset, and MS cases whose mothers had donated blood during pregnancy, by cross-linking a database of MS cases, and a database of mothers of MS cases, to two local biobank cohorts. One of them consisted of blood samples collected during early pregnancy, and one with samples collected during health controls. Levels of 25(OH)D (25-hydroxyvitamin D), RBP (retinol binding protein, a surrogate marker for vitamin A), CRP (C- reactive protein), cotinine (a nicotine metabolite) and anti Epstein-Barr virus nuclear antigen-1 (EBNA-1) antibodies were measured in cases and matched controls. The risk of MS by categories of these exposures was estimated in bi- and multivariable matched logistic regression models.

Results Subjects born in spring had a higher risk of MS, but no influence of early gestational levels of the measured risk factors on the risk of MS in the offspring was observed. In prospective samples from MS cases and controls, 25(OH)D levels ≥75 nmol/l, intermediate RBP levels, and elevated CRP levels in young were associated with a decreased risk of MS. Elevated cotinine levels (suggestive of smoking) and high antibody reactivity against EBNA-1 were associated with an increased risk of MS. All factors but RBP were more clearly associated with MS in young subjects.

Conclusion All factors analyzed in prospectively collected samples were associated with the risk of MS, and taken together, the data indicate that the key etiopathological events that lead to MS occur before the age of 20–30. Study II provides support for trials exploring the primary preventive potential of oral vitamin D supplementation.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2013. , 54 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1545
Keyword [en]
Multiple sclerosis, risk factors in epidemiology, prospective, month of birth, vitamin D, vitamin A, C-reactive protein, hygiene hypothesis, smoking, cotinine, Epstein-Barr virus
National Category
Neurology
Research subject
Epidemiology
Identifiers
URN: urn:nbn:se:umu:diva-64212ISBN: 978-91-7459-545-1 (print)OAI: oai:DiVA.org:umu-64212DiVA: diva2:602356
Public defence
2013-03-01, Hörsal E04, By 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-02-08 Created: 2013-01-21 Last updated: 2013-02-08Bibliographically approved
List of papers
1. Season of birth and multiple sclerosis in Sweden
Open this publication in new window or tab >>Season of birth and multiple sclerosis in Sweden
2010 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 122, no 1, 70-73 p.Article in journal (Refereed) Published
Abstract [en]

This study supports previous results suggesting an association between the risk of MS and the season of birth. Decreased exposure to sun in the winter leading to low vitamin D levels during pregnancy is a possible explanation that needs further research.

Keyword
epidemiology; etiology; month of birth; multiple sclerosis; season of birth; seasonality; vitamin D
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-42291 (URN)10.1111/j.1600-0404.2010.01396.x (DOI)20597868 (PubMedID)
Available from: 2012-11-09 Created: 2011-04-07 Last updated: 2017-12-11Bibliographically approved
2. Vitamin D as a protective factor in multiple sclerosis
Open this publication in new window or tab >>Vitamin D as a protective factor in multiple sclerosis
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2012 (English)In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 79, no 21, 2140-2145 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To examine the association between 25-hydroxyvitamin D (25[OH]D) levels and the risk of multiple sclerosis (MS) in blood samples collected prospectively and during gestation.

Methods: In this nested case-control study, 2 population-based biobanks with 291,500 samples from164,000 persons collected since 1975 in the northern half of Sweden were used. We identified prospectively collected blood samples from MS cases (n = 192, controls matched 2:1) and gestational samples from pregnant mothers where the offspring had later developed MS (n = 37, control mothers matched 5:1). 25(OH)D levels were measured using an ELISA, and the risk of MS was analyzed using matched logistic regression.

Results: Levels of 25(OH)D ≥75 (vs <75) nmol/L in prospectively collected blood samples were associated with a decreased risk of MS (odds ratio [OR] 0.39, 95% confidence interval [CI] 0.16- 0.98). No decrease in MS risk was found in the offspring exposed to gestational 25(OH)D levels ≥75 (vs <75) nmol/L (OR 1.8, 95%CI 0.53-5.8). The prevalence of 25(OH)D levels ≥75 nmol/L in female controls decreased gradually during 1976-2005 (p trend = 0.005).

Conclusion: This study supports the presence of an association between high 25(OH)D levels during the years preceding disease onset and a decreased risk of MS. In the very limited material with samples drawn in early pregnancy, where month-of-birth effects were controlled for, we found no association between gestational 25(OH)D levels and MS risk in the offspring. Decreasing 25(OH) D levels in the population may contribute to explain the increasing MS incidence that is suggested from epidemiologic studies.

National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-63632 (URN)10.1212/WNL.0b013e3182752ea8 (DOI)
Available from: 2013-01-08 Created: 2013-01-03 Last updated: 2017-12-06Bibliographically approved
3. Vitamin A and systemic inflammation as protective factors in multiple sclerosis
Open this publication in new window or tab >>Vitamin A and systemic inflammation as protective factors in multiple sclerosis
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2013 (English)In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 19, no 8, 1046-1051 p.Article in journal (Refereed) Published
Abstract [en]

Background: Vitamin A is important for the immune system, and might suppress inflammatory activity in multiple sclerosis (MS).

Objectives: We aimed to examine if vitamin A levels were associated with MS risk in samples collected prospectively and during gestation.

Methods: We measured Retinol Binding Protein (RBP – a surrogate marker for vitamin A) and high-sensitivity C-reactive protein (hs-CRP) levels, in (1) prospectively collected biobank blood samples from MS cases and controls, and (2) gestational samples where the offspring had later developed MS, and gestational control samples. The risk of MS was calculated using matched multivariable logistic regression adjusted for confounders.

Results: In prospective samples, RBP levels within the second quintile (vs. the first) were associated with a lower MS risk (OR = 0.38, 95% CI 0.19–0.74). No effect on MS risk in the offspring by gestational RBP levels was found. In young subjects hs-CRP levels ≥10 mg/l in prospective samples were associated with a lower MS risk (OR = 0.36, 95% CI 0.14–0.95).

Conclusions: Our results suggest that sub-optimal vitamin A levels may be associated with MS risk. The association between hs-CRP levels and MS risk in young subjects may support the role of the hygiene hypothesis in MS aetiology. 

Place, publisher, year, edition, pages
Sage Publications, 2013
Keyword
Multiple sclerosis, case-control study, risk factors in epidemiology, vitamin a, retinol, c-reactive protein, CRP, hygiene hypothesis
National Category
Neurology
Research subject
Epidemiology
Identifiers
urn:nbn:se:umu:diva-64211 (URN)10.1177/1352458512472752 (DOI)
Available from: 2013-01-21 Created: 2013-01-21 Last updated: 2017-12-06Bibliographically approved
4. Smoking as a risk factor for multiple sclerosis
Open this publication in new window or tab >>Smoking as a risk factor for multiple sclerosis
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2013 (English)In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 19, no 8, 1022-1027 p.Article in journal (Refereed) Published
Abstract [en]

Background: Smoking has been associated with an increased risk for multiple sclerosis, but no studies have measured levels of the nicotine metabolite cotinine in prospectively collected samples to assess exposure.

Objective: To investigate the effects of laboratory defined tobacco use on the risk for multiple sclerosis using prospectively collected biobank blood samples.

Methods: Levels of cotinine were measured in n=192 cases, and n=384 matched controls, using an immunoassay. The risk for multiple sclerosis was estimated using matched logistic regression.

Results: Elevated cotinine levels (≥10 ng/ml) were associated with a significantly increased risk for multiple sclerosis, (odds ratio, OR 1.5, 95% confidence interval, CI 1.0–2.1). This association was only present in young individuals (below median age at blood sampling, <26.4 years), (OR 2.2, 95% CI 1.3–3.8).

Conclusions: This study confirms that smoking is a risk factor for multiple sclerosis. It has the advantage of using analyses of cotinine levels in samples that were collected several years before disease onset, thus excluding any risk for recall bias and minimising the risk for reversed causation. Our results also suggest that the smoking related immunological events that contribute to the development of multiple sclerosis occur early in life.

Place, publisher, year, edition, pages
Sage Publications, 2013
Keyword
Multiple sclerosis, case control study, risk factors in epidemiology, smoking
National Category
Neurology
Research subject
Epidemiology
Identifiers
urn:nbn:se:umu:diva-63742 (URN)10.1177/1352458512470862 (DOI)
Note

First published online December 20th, 2012.

Available from: 2013-01-11 Created: 2013-01-07 Last updated: 2017-12-06Bibliographically approved
5. Epstein-Barr virus antibodies and vitamin D in prospective multiple sclerosis biobank sampels
Open this publication in new window or tab >>Epstein-Barr virus antibodies and vitamin D in prospective multiple sclerosis biobank sampels
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2013 (English)In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 19, no 12, 1587-1591 p.Article in journal (Refereed) Published
Abstract [en]

Background: Increased antibody reactivity against Epstein-Barr Nuclear Antigen-1 (EBNA-1) has been associated with an increased risk for MS, and high levels of 25-Hydroxyvitamin D (25[OH]D) have been associated with a lower risk for MS. Interaction between these two factors has been proposed.

Objectives: To examine the association between antibody reactivity against EBNA-1 and five EBNA-1 domains, and the risk for multiple sclerosis (MS), and to examine if these antibodies and 25(OH)D status interact regarding MS risk in prospectively collected blood samples.

Methods: Antibody reactivity (as specified above) and 25(OH)D levels were measured using ELISAs in n=192 MS cases and n=384 matched controls. The risk for MS was analysed using matched logistic regression.

Results: The risk for MS increased across tertiles of antibody reactivity against EBNA-1, domain EBNA-1402–502, and domain EBNA-1385–420; p trend <0.001. The risk increase was most pronounced for EBNA-1385–420. In young individuals (below median age at sampling, <26.4 years) these associations were stronger, and 25(OH)D levels correlated inversely to antibody reactivity against EBNA-1 and the EBNA-1 domains.

Conclusions: We confirm that increased antibody reactivity against EBNA-1 is a risk factor for MS. Our findings in young individuals suggest that 25(OH)D status might influence the immune response towards Epstein-Barr virus, and thereby modulate MS risk.

Place, publisher, year, edition, pages
Sage Publications, 2013
Keyword
Multiple sclerosis, Case control study, Risk factors in epidemiology, Epstein-Barr virus (EBV), Epstein-Barr Nuclear Antigen-1 (EBNA-1), Vitamin D (25[OH]D)
National Category
Neurology
Research subject
Epidemiology
Identifiers
urn:nbn:se:umu:diva-63746 (URN)10.1177/1352458513483888 (DOI)000325696100008 ()
Available from: 2013-02-11 Created: 2013-01-07 Last updated: 2017-12-06Bibliographically approved

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