Diabetes Mellitus, Glycemic Traits, and Cerebrovascular Disease: A Mendelian Randomization Study

Abstract

Objective: We employed Mendelian randomization to explore the effects of genetic predisposition to type 2 diabetes (T2D), hyperglycemia, insulin resistance, and pancreatic β-cell dysfunction on risk of stroke subtypes and related cerebrovascular phenotypes.

Methods: We selected instruments for genetic predisposition to T2D (74,124 cases, 824,006 controls), HbA1c levels (n = 421,923), fasting glucose levels (n = 133,010), insulin resistance (n = 108,557), and β-cell dysfunction (n = 16,378) based on published genome-wide association studies. Applying 2-sample Mendelian randomization, we examined associations with ischemic stroke (60,341 cases, 454,450 controls), intracerebral hemorrhage (1,545 cases, 1,481 controls), and ischemic stroke subtypes (large artery, cardioembolic, small vessel stroke), as well as with related phenotypes (carotid atherosclerosis, imaging markers of cerebral white matter integrity, and brain atrophy).

Results: Genetic predisposition to T2D and higher HbA1c levels were associated with higher risk of any ischemic stroke, large artery stroke, and small vessel stroke. Similar associations were also noted for carotid atherosclerotic plaque, fractional anisotropy, a white matter disease marker, and markers of brain atrophy. We further found associations of genetic predisposition to insulin resistance with large artery and small vessel stroke, whereas predisposition to β-cell dysfunction was associated with small vessel stroke, intracerebral hemorrhage, lower gray matter volume, and total brain volume.

Conclusions: This study supports causal effects of T2D and hyperglycemia on large artery and small vessel stroke. We show associations of genetically predicted insulin resistance and β-cell dysfunction with large artery and small vessel stroke that might have implications for antidiabetic treatments targeting these mechanisms.

Classification of evidence: This study provides Class II evidence that genetic predisposition to T2D and higher HbA1c levels are associated with a higher risk of large artery and small vessel ischemic stroke.

Figure 1. Mendelian Randomization Associations of Genetic Predisposition to Type 2 Diabetes Mellitus and HbA1c Levels Among Diabetic and Nondiabetic Individuals

(A) Type 2 diabetes. (B) HbA1c levels. Results derived from random-effects inverse-variance weighted analyses. Full circles correspond to statistically significant association estimates at a false discovery rate–adjusted p value < 0.05. CI = confidence interval; OR = odds ratio.

Figure 2. Mendelian Randomization Associations of Genetically Predicted Insulin Resistance and β-Cell Dysfunction With Stroke Subtypes

(A) Results derived from random-effects inverse-variance weighted analyses. (B) Heatmap of the associations between clusters of diabetic endophenotypes related to β-cell dysfunction and insulin resistance with the risk of stroke subtypes. Full colored circles in A correspond to statistically significant association estimates at a false discovery rate (FDR)–adjusted p value < 0.05. CI = confidence interval.