Investigating the causal mediating effect of type 2 diabetes on the relationship between traits and systolic blood pressure: A two-step Mendelian randomization study.

Background: Type 2 diabetes mellitus (T2DM) and hypertension commonly coexist, and we presumed that T2DM might mediate the relationship between some shared risk factors and systolic blood pressure (SBP). Methods: The causal association between T2DM and SBP was first confirmed using Mendelian randomization (MR) analyses, and a two-step MR design was then used to test the causal mediating effect of T2DM on the relationship between 107 traits and SBP using summary statistics from genome-wide association studies. Results: T2DM was causally associated with SBP. The univariable MR of the two-step causal mediation analyses suggested that 44 and 45 of the 107 traits had causal associations with T2DM and SBP, respectively. Five of the 27 traits that were significantly associated with both T2DM and SBP could not be reversely altered by T2DM and were included in the second step of the causal mediation analyses. The results indicated that most of the investigated traits causally altered SBP independent of T2DM, but the partial causal mediating effect of T2DM on the association between fasting insulin and SBP was successfully identified with a mediation proportion of 33.6%. Conclusions: Our study provides novel insights into the role of risk factors in the comorbidity of T2DM and high blood pressure, which is important for long-term disease prevention and management.