Journal Article

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

Mitchell, Ruth E., Polychronakos, Constantin, Forgetta, Vince, Timpson, Nicholas J., Manousaki, Despoina, Ross, Stephanie, Smith, George Davey, Richards, J Brent, Harroud, Adil

2021

Overview

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). 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Biology and Life Sciences / Biomarkers / Causality / Clinical trials / Complications and side effects / Diabetes / Diabetes mellitus (insulin dependent) / Diabetes Mellitus, Type 1 - complications / Diabetes Mellitus, Type 1 - etiology / Diabetes Mellitus, Type 1 - genetics / Diabetes Mellitus, Type 2 - complications / Epidemiology / Genetic aspects / Genetic diversity / Genetic variance / Genome-wide association studies / Genome-Wide Association Study / Genomes / Health care / Humans / Hypotheses / Immune system / Medicine and Health Sciences / Mendelian Randomization Analysis - methods / Phenotype / Physical sciences / Polymorphism, Single Nucleotide - genetics / Research and Analysis Methods / Risk Factors / Single-nucleotide polymorphism / Type 1 diabetes / Ultraviolet radiation / Vitamin D / Vitamin D - blood / Vitamin D deficiency / Vitamin D Deficiency - blood / Vitamin D Deficiency - genetics / Vitamin deficiency