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Randomized Controlled Trial
. 2021 Feb 25;18(2):e1003536.
doi: 10.1371/journal.pmed.1003536. eCollection 2021 Feb.

Vitamin D levels and risk of type 1 diabetes: A Mendelian randomization study

Despoina Manousaki  1   2 , Adil Harroud  3   4 , Ruth E Mitchell  5   6 , Stephanie Ross  7 , Vince Forgetta  8 , Nicholas J Timpson  5 , George Davey Smith  5   6 , Constantin Polychronakos  9   10   11 , J Brent Richards  8   9   12   13   14
Affiliations
Randomized Controlled Trial

Vitamin D levels and risk of type 1 diabetes: A Mendelian randomization study

Despoina Manousaki et al. PLoS Med. .

Erratum in

Abstract

Background: Vitamin D deficiency has been associated with type 1 diabetes in observational studies, but evidence from randomized controlled trials (RCTs) is lacking. The aim of this study was to test whether genetically decreased vitamin D levels are causally associated with type 1 diabetes using Mendelian randomization (MR).

Methods and findings: For our two-sample MR study, we selected as instruments single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels in a large vitamin D genome-wide association study (GWAS) on 443,734 Europeans and obtained their corresponding effect estimates on type 1 diabetes risk from a large meta-analysis of 12 type 1 diabetes GWAS studies (Ntot = 24,063, 9,358 cases, and 15,705 controls). In addition to the main analysis using inverse variance weighted MR, we applied 3 additional methods to control for pleiotropy (MR-Egger, weighted median, and mode-based estimate) and compared the respective MR estimates. We also undertook sensitivity analyses excluding SNPs with potential pleiotropic effects. We identified 69 lead independent common SNPs to be genome-wide significant for 25OHD, explaining 3.1% of the variance in 25OHD levels. MR analyses suggested that a 1 standard deviation (SD) decrease in standardized natural log-transformed 25OHD (corresponding to a 29-nmol/l change in 25OHD levels in vitamin D-insufficient individuals) was not associated with an increase in type 1 diabetes risk (inverse-variance weighted (IVW) MR odds ratio (OR) = 1.09, 95% CI: 0.86 to 1.40, p = 0.48). We obtained similar results using the 3 pleiotropy robust MR methods and in sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes. Our findings indicate that decreased vitamin D levels did not have a substantial impact on risk of type 1 diabetes in the populations studied. Study limitations include an inability to exclude the existence of smaller associations and a lack of evidence from non-European populations.

Conclusions: Our findings suggest that 25OHD levels are unlikely to have a large effect on risk of type 1 diabetes, but larger MR studies or RCTs are needed to investigate small effects.

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Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests:JBR has worked as a consultant to GlaxoSmithKline and Deerfield Capital.GDS is a member of the Editorial Board of PLOS Medicine.

Figures

Fig 1
Fig 1. Forest plot of the MR study investigating the effect of 25OHD on type 1 diabetes.
Forest plot of the main study and of the sensitivity analysis excluding proxy SNPs. 25OHD, 25-hydroxyvitamin D; MR, Mendelian randomization; SNP, single nucleotide polymorphism.
Fig 2
Fig 2. Forest plot of the MR sensitivity analyses excluding SNPs with possible pleiotropic effects.
The odds ratios for type 1 diabetes are reported for a 1 standard deviation decrease in 25OHD on the log scale. 25OHD, 25-hydroxyvitamin D; CI, confidence intervals; MR, Mendelian randomization; OR, odds ratio; SNP, single nucleotide polymorphism.
Fig 3
Fig 3. Scatter plot of the main MR study investigating the effect of 25OHD on type 1 diabetes.
The x-axis represents the genetic association with 25OHD levels; the y-axis represents the genetic association with risk of type 1 diabetes. Each line represents a different MR method. 25OHD, 25-hydroxyvitamin D; MR, Mendelian randomization.
See this image and copyright information in PMC

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