期刊
NEUROLOGY
卷 96, 期 13, 页码 E1732-E1742出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0000000000011555
关键词
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资金
- Onassis Foundation
- German Academic Exchange Service (DAAD)
- European Union [666881, 667375]
- DFG as part of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy) [390857198]
- Corona Foundation
- Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain)
- LMU Munich
- Cambridge University
- British Heart Foundation Programme Grant [RG/16/4/32,218]
- UK Medical Research Council [MC_UU_12,015/1, MC_UU_00,006/1]
- NIHR Cambridge Biomedical Research Centre [IS-BRC-1215-20,014]
- CRC 1123
- MRC [MC_UU_00006/1] Funding Source: UKRI
This study using Mendelian randomization found that genetic predisposition to type 2 diabetes and higher HbA1c levels are associated with an increased risk of large artery and small vessel stroke, while genetic predisposition to insulin resistance and beta-cell dysfunction are also linked to different stroke subtypes and cerebrovascular phenotypes.
Objective We employed Mendelian randomization to explore the effects of genetic predisposition to type 2 diabetes (T2D), hyperglycemia, insulin resistance, and pancreatic beta-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 beta-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 beta-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 beta-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.
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