# Genetically Predicted Serum 25‐Hydroxyvitamin D Concentrations in Related to Type 2 Diabetes Mellitus: A Mendelian Randomization Study

## TL;DR

This study finds that higher genetically predicted levels of vitamin D are linked to a lower risk of type 2 diabetes, using genetic data from over 800,000 people.

## Contribution

The study provides causal evidence that higher serum 25-hydroxyvitamin D levels are associated with reduced type 2 diabetes risk using Mendelian randomization.

## Key findings

- Genetically predicted higher serum 25(OH)D levels are consistently associated with reduced risk of T2DM in both UVMR and MVMR analyses.
- A 1-SD increase in genetically predicted serum 25(OH)D levels is linked to an odds ratio of 0.67 for T2DM.
- Vitamins B6, B9, B12, and C do not show significant associations with T2DM.

## Abstract

In several observational studies, vitamins B6, B9, B12, C and 25‐hydroxyvitamin D[25(OH)D] concentrations were associated with type 2 diabetes mellitus (T2DM). Although vitamins play a role in the development of type 2 diabetes mellitus (T2DM), their associations remain unclear.

This study employed Mendelian randomisation (MR) to explore the causal relationships between circulating concentrations of vitamins B6, B9, B12, C, 25‐hydroxyvitamin D and T2DM.

Single‐nucleotide polymorphisms (SNPs) linked to vitamin B6, vitamin B9, vitamin B12, vitamin C and 25(OH)D levels were used as instrumental variables (IVs) in this study. We have two outcomes related to T2DM derived from two genome‐wide association studies (GWAS). The first study, referenced by PMID: 3417140, encompasses a cohort of 406,831 individuals of European descent. The second study, identified by PMID: 29892013, includes a sample size of 468,298 Europeans.

Both univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) analyses demonstrate that genetically predicted elevated levels of serum 25(OH)D are consistently associated with a reduced risk of T2DM. In the UVMR analyses, A 1‐SD increase in genetically predicted serum 25(OH)D levels, the inverse‐variance weighted (IVW) p = 3.8 × 10−7, p

fdr
 = 7.6 × 10−7, the odds ratio(OR) of T2DM (GCST90013942) was 0.67, 95% confidence interval (CI): 0.57–0.78. Furthermore, a 1‐SD increase in genetically predicted serum 25(OH)D levels was associated with an OR of 0.987 for T2DM (GCST90029024), the IVW p = 1.1 × 10−4, p

fdr
 = 1.1 × 10−4 with a 95% CI of 0.981–0.994. In the MVMR analyses, genetically predicted higher serum 25(OH)D levels were associated with a decreased risk of T2DM by the IVW p = 1.2 × 10−5, p

fdr
 = 5.9 × 10−5 in GCST90013942 and IVW p = 4.9 × 10−4, p

fdr
 = 2.5 × 10−3 in GCST90029024. In contrast, levels of vitamins B6, B9, B12, and C did not domenstrate a significant association with T2DM.

Our research reveals that higher circulating serum 25(OH)D levels reduce the possibility of T2DM.

Recent studies have demonstrated an association between the concentrations of vitamins B6, B9, B12, C, and 25‐hydroxyvitamin D and the incidence of type 2 diabetes mellitus. This study utilized Mendelian randomization (MR) to investigate the causal relationships between circulating levels of these vitamins and T2DM. Single nucleotide polymorphisms associated with levels of vitamins B6, B9, B12, C, and 25‐hydroxyvitamin D were employed as instrumental variables in this study. Both univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) analyses indicate that genetically predicted higher serum levels of 25‐hydroxyvitamin D are consistently linked to a decreased risk of type 2 diabetes mellitus. Our study indicates that elevated levels of circulating serum 25‐hydroxyvitamin D are associated with a decreased risk of developing type 2 diabetes mellitus.