Genetically Predicted Type 2 Diabetes Mellitus Mediates the Causal Association Between Plasma Uric Acid and Ischemic Stroke

Objective: This study conducts a systematic investigation into the causal relationships between plasma uric acid levels and subtypes of ischemic stroke (IS), as well as the extent to which Type 2 diabetes mellitus (T2DM) mediates this relationship.

Background: There is a known association between Uric acid and IS but whether they have a causal relationship remains unclear. This study aims to determine whether a genetic predisposition to uric acid is causally linked to IS, including three subtypes, and to determine the mediating role of T2DM.

Methods: Bidirectional Mendelian randomization (MR) analyses was initially used to explore the causal relationship between uric acid and three subtypes of IS. Two-step MR methods were then used to investigate the role of T2DM in mediating the effect of uric acid and IS with its subtypes.

Results: A primary analysis showed uric acid had a markedly causal association with IS (IVW, OR 1.23; 95 % CI, 1.13 - 1.34; p = 6.39 × 10), and two subtypes of IS, Large-vessel atherosclerotic stroke LAS (IVW, OR 1.25; 95 % CI, 1.03 - 1.53; p = 0.026) and small vessel stroke (SVS) (IVW, OR 1.20; 95 % CI, 1.00 - 1.43; p = 0.049), but not with cardioembolic stroke (CES)(IVW, OR 1.00; 95 % CI, 0.87 - 1.15; p = 0.993). Two-step MR results showed that T2DM mediated the association between uric acid and LAS and SVS, accounting for 13.85 % (p = 0.025) and 13.57 % (p = 0.028), respectively.

Conclusions: The study suggests that genetic predisposition to uric acid is linked to a greater risk of IS, especially LAS and SVS. T2DM might mediate a significant proportion of the associations between uric acid and LAS as well as SVS.