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Published on: December 9, 2015
Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk
Brooke Rhead1, Maria Bäärnhielm1, Milena Gianfrancesco1
1Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.
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.
Insights
Low vitamin D levels (serum 25(OH)D) causally increase the risk of developing multiple sclerosis (MS). This study used genetic data to confirm that low vitamin D is a risk factor for MS, independent of other factors.
Area of Science:
- Neuroimmunology
- Nutritional Neuroscience
- Genetic Epidemiology
Background:
- Low serum 25(OH)D levels are linked to increased multiple sclerosis (MS) risk.
- Previous studies suggest a correlation, but causal links and confounding factors remain unclear.
Purpose of the Study:
- To determine the causal effect of low serum 25(OH)D on MS susceptibility.
- To exclude confounding from environmental, lifestyle factors, and reverse causality.
Main Methods:
- Mendelian randomization (MR) analyses utilizing 3 single nucleotide polymorphisms as instrumental variables for serum 25(OH)D.
- Logistic regression models in two distinct populations (Kaiser Permanente Northern California and Swedish MS studies) to assess the IV's effect on MS risk, age at onset, and disease severity.
- Adjustments for multiple covariates including sex, smoking, education, BMI, and genetic risk scores for MS and HLA-DRB1*15:01.
Main Results:
- MR analyses indicated that higher serum 25(OH)D levels are associated with decreased MS risk (OR=0.79 in US, OR=0.86 in Swedish population).
- A meta-analysis of both populations yielded a combined OR of 0.85 (p=0.003), strongly supporting an inverse relationship between 25(OH)D and MS risk.
- No significant association was found between serum 25(OH)D levels and MS age at onset or disease severity.
Conclusions:
- The study provides robust evidence for a causal relationship between low serum 25(OH)D concentration and increased MS susceptibility.
- This causal link is independent of known MS risk factors and environmental influences.
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