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

Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk.

ObjectiveWe sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality.MethodsWe conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18-20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles.ResultsFindings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p = 0.04, 95% confidence interval (CI): 0.64-0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p = 0.03, 95% CI: 0.76-0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p = 0.003, 95% CI: 0.76-0.94). No association was observed for age at onset or disease severity.ConclusionsThese results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors

Samis in the city. A qualitative study of mental health and well-being among Samis in Stockholm

ABSTRACTIndigenous people globally suffer from poorer health than majority populations. For the Sami, the indigenous people living in the north of Norway, Sweden, Finland and Russia, physical health conditions seem to be comparable to the population in general, but there are concerns about mental health. Studies have shown a higher risk of suicide, especially for young men active in traditional reindeer herding in the north. There is less knowledge about the mental health of Samis that have migrated to the cities. In this study, we interviewed 25 Samis, recruited through convenience sampling in the Stockholm area, about their perceptions of health and well-being, the importance of the Sami background and culture, their views of mental health services and the need of adapting them to Sami needs. Throughout the process, the researchers collaborated closely with the Stockholm Sami Association, in an approach of participatory research. The interviews were analysed with thematic analysis. For the participants, a secure Sami identity and being treated with respect for their identity was seen as essential for mental health and well-being. Informants’ emphasis on respect for their Sami identity and belonging can be seen as a call for restoration of basic human rights. Historical experiences, current harassments and political decisions affected their health. The informants wished caregivers to increase their knowledge of Sami history and traditions

Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk

OBJECTIVE: We sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality. METHODS: We conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18–20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles. RESULTS: Findings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p = 0.04, 95% confidence interval (CI): 0.64–0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p = 0.03, 95% CI: 0.76–0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p = 0.003, 95% CI: 0.76–0.94). No association was observed for age at onset or disease severity. CONCLUSIONS: These results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors

Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS

ObjectiveTo utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS).MethodsWe constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820).ResultsMeta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; p = 0.02) after controlling for sex, genetic ancestry, HLA-DRB1*15:01, and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; p = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model.ConclusionsWe provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS