Using Mendelian Randomization to Elucidate the Role of Vitamin D in Multiple Sclerosis

• Main Author: Mokry, Lauren E
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2016
• Subjects: Clinical trials; Consortia; Epidemiology; Etiology; Genomes; Medicine; Multiple sclerosis; Nutrition; Risk factors; Vitamin D
• ISBN: 9798597037417

Background: Observational studies have long reported an association between decreased vitamin D and increased risk of multiple sclerosis (MS). However since it is difficult to fully protect these approaches from confounding and reverse causation, it remains unclear whether vitamin D is a causal risk factor in MS etiology.Objectives: To review the current literature of the association between vitamin D and MS and discuss the limitations of these previous approaches. Next, to introduce Mendelian randomization (MR) and apply its principles to investigate whether the genetic determinants of vitamin D are associated with MS susceptibility.Methods: PubMed was used to search for relevant ecological, observational and randomized controlled trials. For our MR analysis, we first selected single nucleotide polymorphisms (SNPs) that achieved genome-wide significant (p-value < 5 × 10–8) for 25-hydroxyvitamin D (25OHD), the clinical determinant of vitamin D status, in the SUNLIGHT consortium (N= 33,996). We then obtained effect sizes for these SNPs upon MS in the International Multiple Sclerosis Genetics Consortium (IMSGC), the largest genome-wide association study for MS (including up to 14,498 cases and 24,091 controls). MR estimates were obtained by weighting each SNP's effect on MS by its effect on 25OHD, with estimates pooled to provide a summary measure of the effect of genetically lowered vitamin D upon risk of MS.Results: Results of our MR analysis using four vitamin D associated SNPs, demonstrated that a 1 standard deviation decrease in natural log 25OHD increased odds of MS by 2 fold (OR = 2.02, 95% CI: 1.7–2.5; p = 7.7 × 10−12; l2 = 63%, 95% CI: 0%–88%).Conclusions: Using MR, our findings support vitamin D as a causal risk factor for MS, substantiating conclusions first suggested by observational analyses. This provides rationale to promote vitamin D awareness among individual at risk for MS. Whether vitamin D supplementation can prevent MS warrants further investigation by long-term clinical trials.