Introduction: This study aims to investigate the causal relation of genetically conferred circulating phylloquinone levels and the risk of type 2 diabetes (T2D) via a Mendelian Randomization approach.
Methods: We used data from the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study comprising 10,071 diabetes cases and 13,309 subcohort members from eight European countries. We calculated a weighted genetic risk score (wGRS) including four SNPs (rs2192574, rs6862071, rs4645543 and rs2108622) likely to be related to circulating phylloquinone levels from a genome wide association study. Inverse-variance weighted (IVW) analysis was used to obtain a Hazard Ratio (HR) for the unconfounded relation between circulating phylloquinone levels and T2D incidence. All analyses were adjusted for sex, center, principal components of ancestry, genetic platform, triglycerides and hours fasting. Furthermore, we assessed the robustness of our results with a MR Egger analyses. In follow-up analyses, we have included data from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, increasing our dataset to 21,571 participants with diabetes.
Results: The median follow-up time was 10.9 years. In IVW analysis, genetically conferred higher circulating phylloquinone levels were associated with a reduced risk of T2D with a HR of 0.87 (0.78;0.97) for every ln-nmol/L increase in circulating phylloquinone. The MR Egger method resulted in a HR of 0.88 (0.72;1.08).Adding DIAGRAM data resulted in a summary odds ratio of 0.90 (0.81;1.00).
Conclusion: Our study suggests that the association between higher circulating phylloquinone levels and lower T2D incidence may be causal.