Association Between Circulating Vitamin K Levels, Gut Microbiome, and Type 1 Diabetes: A Mendelian Randomization Study

Abstract

Background/objectives: Nutritional deficiencies have been proposed as possible etiological causes for autoimmune diseases, among which type 1 diabetes (T1D). Vitamin K (VK) has potentially positive effects on type 2 diabetes, but its role on T1D in humans remains largely unknown. We aimed to examine the presence of a causal association between VK and T1D using a Mendelian randomization (MR) approach.

Methods: Genetic variants from a genome-wide association study (GWAS) for VK (N = 2138 Europeans) were used as instruments in our two-sample MR study to investigate whether circulating VK levels are causally associated with the risk of T1D in a large European T1D GWAS cohort (18,942 cases/520,580 controls). Through a multivariable MR (MVMR), the effects of both VK and specific gut microbiota on T1D were investigated given that the gut microbiome synthesizes VK.

Results: We found that changes in levels of circulating VK did not affect T1D risk in our univariate two-sample MR, but this study had limited power to detect small effects of VK (OR for T1D of less than 0.8). However, our MVMR indicated a suggestive association of VK with the risk of T1D adjusting for two different gut microbiome populations.

Conclusions: In conclusion, VK levels are unlikely to significantly affect the risk of T1D, but small effects cannot be excluded, and the role of gut microbiome in this association should be further investigated.

Keywords: GWAS; mendelian randomization; type 1 diabetes; vitamin K.

Figure 1

Flowchart with the design of our MR study.

Figure 2

MR direct acyclic graph (DAG) of our study.

Figure 3

Forest plots with the results of the main MR analysis. The results represent the MR OR for T1D per SD increase in circulating VK1 levels measured according to three GWAS models and using various MR methods.

Figure 4

Direct acyclic graph (DAG) of our MVMR analysis, including gut microbiome as a second exposure. If exposure 2 (gut microbiome) is a mediator, then the red line (effect β₂₎ shows the indirect effect of exposure 1 (VK1) on the outcome Y (T1D). If exposure 2 (gut microbiome) is a collider (blue line between Y and X2), then accounting for the β₂ can induce a spurious association between exposure 1 (VK1) and the outcome Y (T1D).