Vitamin D and multiple sclerosis : epidemiological studies on environmental and genetic risk factors

Background: Multiple sclerosis (MS) is an autoimmune inflammatory neurological disease with complex aetiology where the causes are not completely known. The main aim of this thesis was to investigate the influence of vitamin D on the risk of developing MS.

Methods: The papers in this thesis are based on data from a nationwide population-based case–control study, the Epidemiological Investigation of Multiple Sclerosis (EIMS) study. The source population for the EIMS study is the Swedish population, aged 16–70 years, in defined areas of Sweden. The cases are diagnosed at neurological centres according to the McDonalds criteria, and included in the study within 2 years after diagnosis, and the controls are selected randomly from the population register and matched according to sex and age and residential area at the time of diagnosis of the case. All study participants are invited to respond to an extensive questionnaire regarding environmental and lifestyle factors and to give blood samples. The response proportion has been 91% for the cases and 70% for the controls for the questionnaire and 94% and 57% for the blood samples, respectively. The fourth paper in this thesis is based on data from the EIMS study as well as data from another Swedish case–control study, the Genes and Environment in Multiple Sclerosis (GEMS) study, and the American Kaiser Permanente Medical Plan Northern California (KPNC) study. In these studies, prevalent MS cases aged 18 years and above (and white non-hispanic individuals for the KPNC study), with a verified diagnosis according to McDonalds criteria or International Classification of Diseases (ninth revision), were invited to participate and exposure information was collected through questionnaires and blood sampling.

Results: Low sunlight exposure was associated with increased MS risk, where self-reported no voluntary sun exposure was associated with a 60% increased risk of developing MS compared to daily sun exposure. Low vitamin D levels were also associated with increased MS risk (odds ratio (OR) 1.4, 95% confidence interval (CI) 1.2–1.7), with no interaction with HLA-DRB1*15. High fatty fish intake, i.e. at least once a week, which is a source of vitamin D, was significantly associated with decreased MS risk (OR 0.82, 95% CI 0.68–0.98). To investigate the timing of the exposure of vitamin D we evaluated the association between vitamin D levels in blood samples taken at birth and later risk of developing MS and did not find any sign of an association. Finally, we investigated whether or not the association seen in our studies between vitamin D deficiency and MS risk was a causal association. We calculated a genetic risk score for vitamin D levels based on three genetic polymorphisms, where a higher score corresponded to higher vitamin D levels. We found that a higher score was associated with decreased MS risk (OR 0.85, 95% CI 0.76–0.94).

Conclusion: Vitamin D deficiency seems to be a causal risk factor for MS, but the susceptibility period does not appear to be during the neonatal stage. Oral vitamin D intake may be protective and sunlight exposure may impact MS risk with no influence from HLA- DRB1*15 status.

List of scientific papers

I. Maria Bäärnhielm, Anna Karin Hedström, Ingrid Kockum, Emilie Sundqvist, Sven A. Gustafsson, Jan Hillert, Tomas Olsson, Lars Alfredsson. Sunlight is associated with decreased multiple sclerosis risk: no interaction with human leukocyte antigen-DRB1*15. European Journal of Neurology 2012 Jul;19(7):955-962.
https://doi.org/10.1111/j.1468-1331.2011.03650.x

II. Maria Bäärnhielm, Tomas Olsson, Lars Alfredsson. Fatty fish is associated with decreased occurrence of multiple sclerosis. Multiple Sclerosis Journal, 2014 May; 20(6):726-732.
https://doi.org/10.1177/1352458513509508

III. Peter Ueda, Farshid Rafatnia, Maria Bäärnhielm, Robin Fröbom, Greg Korzunowicz, Ragnar Lönnerbro, Anna Karin Hedström, Darryl Eyles, Tomas Olsson, Lars Alfredsson. Neonatal vitamin D status and risk of multiple sclerosis. Annals of Neurology 2014 Sep;76(3):338-346.
https://doi.org/10.1002/ana.24210

IV. Brooke Rhead, Maria Bäärnhielm, Milena Gianfrancesco, Amanda Mok, Xiaorong Shao, Hong Quach, Ling Shen, Catherine Schaefer, Jenny Link, Alexandra Gyllenberg, Anna Karin Hedström, Tomas Olsson, Jan Hillert, Ingrid Kockum, Maria Glymour, Lars Alfredsson, Lisa F. Barcellos. Mendelian randomization provides evidence for a causal effect of low vitamin D on multiple sclerosis risk. [Manuscript]