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

Author summary Why was this study done? Observational epidemiological studies have associated low vitamin D levels with risk of type 1 diabetes; however, these studies are susceptible to confounding and reverse causation, and thus it remains unclear whether these associations are accurate. To our knowledge, there are no randomized controlled trials published to date on this topic. If vitamin D insufficiency did cause type 1 diabetes, this would be of clinical relevance for type 1 diabetes prevention in high-risk individuals, since vitamin D insufficiency is common and safely correctable. What did researchers do and find? We applied a Mendelian randomization study design to understand if vitamin D levels are associated with a higher risk of type 1 diabetes. This approach offers an alternative analytical technique able to reduce conventional patterns of confounding and reverse causation and reestimate observations in a framework allowing causal inference. Our study did not find evidence in support of a large effect of vitamin D levels on type 1 diabetes. However, the findings do not exclude the possibility that there may be smaller effects than we could not detect. What do these findings mean? Our findings suggest that the previous epidemiological associations between vitamin D and type 1 diabetes could be due to confounding factors, such as latitude and exposure to sunlight. Our results do not support increasing vitamin D levels as a strategy to decrease the risk of type 1 diabetes. 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.

Automated summary

By applying a Mendelian randomization study design, researchers found no substantial impact of vitamin D levels on the risk of type 1 diabetes. The results suggest that previous epidemiological associations may be influenced by confounding factors, and do not support increasing vitamin D levels as a strategy to decrease the risk of type 1 diabetes.