Diabetes Mellitus, Glycemic Traits, and Cerebrovascular Disease: A Mendelian Randomization Study.
Atrophy
/ epidemiology
Blood Glucose
/ metabolism
Brain
/ diagnostic imaging
Carotid Artery Diseases
/ epidemiology
Cerebral Hemorrhage
/ epidemiology
Cerebrovascular Disorders
/ epidemiology
Diabetes Mellitus, Type 2
/ epidemiology
Genetic Predisposition to Disease
Glycated Hemoglobin
/ metabolism
Humans
Hyperglycemia
/ epidemiology
Insulin Resistance
/ genetics
Insulin-Secreting Cells
Ischemic Stroke
/ epidemiology
Mendelian Randomization Analysis
White Matter
/ diagnostic imaging
Journal
Neurology
ISSN: 1526-632X
Titre abrégé: Neurology
Pays: United States
ID NLM: 0401060
Informations de publication
Date de publication:
30 03 2021
30 03 2021
Historique:
received:
08
04
2020
accepted:
23
12
2020
pubmed:
27
1
2021
medline:
13
4
2021
entrez:
26
1
2021
Statut:
ppublish
Résumé
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. 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). 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. 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. 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.
Identifiants
pubmed: 33495378
pii: WNL.0000000000011555
doi: 10.1212/WNL.0000000000011555
pmc: PMC8055310
doi:
Substances chimiques
Blood Glucose
0
Glycated Hemoglobin A
0
hemoglobin A1c protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1732-e1742Subventions
Organisme : British Heart Foundation
ID : RG/13/13/30194
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK117445
Pays : United States
Organisme : British Heart Foundation
ID : RG/16/4/32218
Pays : United Kingdom
Organisme : Department of Health
ID : IS-BRC-1215-20014
Pays : United Kingdom
Organisme : British Heart Foundation
ID : CH/12/2/29428
Pays : United Kingdom
Organisme : NIEHS NIH HHS
ID : P30 ES010126
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00006/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12015/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/18/13/33946
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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