Mechanisms and treatment of ischaemic stroke—insights from genetic associations

Markus, Hugh S.; Bevan, Steve

doi:10.1038/nrneurol.2014.196

Cited by 48 publications

(43 citation statements)

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“…About 80% of all strokes are ischemic, 1 but this term describes a syndrome caused by a number of different pathologies, which may have different treatments. 2 The major etiologies of ischemic stroke are large artery atherosclerosis (large artery stroke), small vessel atherosclerosis (small vessel stroke), and cardioembolism (cardioembolic stroke). Recent data from genomewide association studies (GWAS) have shown that these subtypes have distinctive risk factor profiles and, by implication, diverse pathophysiologic bases.…”

Section: Discussionmentioning

confidence: 99%

Type 2 diabetes, glucose, insulin, BMI, and ischemic stroke subtypes

Larsson¹,

Scott²,

Traylor³

et al. 2017

Neurology

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Objective: To implement a mendelian randomization (MR) approach to determine whether type 2 diabetes mellitus (T2D), fasting glucose, fasting insulin, and body mass index (BMI) are causally associated with specific ischemic stroke subtypes.Methods: MR estimates of the association between each possible risk factor and ischemic stroke subtypes were calculated with inverse-variance weighted (conventional) and weighted median approaches, and MR-Egger regression was used to explore pleiotropy. The number of single nucleotide polymorphisms (SNPs) used as instrumental variables was 49 for T2D, 36 for fasting glucose, 18 for fasting insulin, and 77 for BMI. Genome-wide association study data of SNPstroke associations were derived from METASTROKE and the Stroke Genetics Network (n 5 18,476 ischemic stroke cases and 37,296 controls).Results: Conventional MR analysis showed associations between genetically predicted T2D and large artery stroke (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.16-1.40, p 5 3.3 3 10 27 ) and small vessel stroke (OR 1.21, 95% CI 1.10-1.33, p 5 8.9 3 10 25 ) but not cardioembolic stroke (OR 1.06, 95% CI 0.97-1.15, p 5 0.17). The association of T2D with large artery stroke but not small vessel stroke was consistent in a sensitivity analysis using the weighted median method, and there was no evidence of pleiotropy. Genetically predicted fasting glucose and fasting insulin levels and BMI were not statistically significantly associated with any ischemic stroke subtype. Conclusions:This study provides support that T2D may be causally associated with large artery stroke. Neurology ® 2017;89:454-460 GLOSSARY BMI 5 body mass index; CI 5 confidence interval; GWAS 5 genome-wide association studies; MR 5 mendelian randomization; NINDS 5 National Institute of Neurologic Disorders and Stroke; 1KG 5 1000 Genomes; OR 5 odds ratio; SiGN 5 Stroke Genetics Network; SNP 5 single nucleotide polymorphism; TOAST 5 Trial of Org 10172 in Acute Stroke Treatment; T2D 5 type 2 diabetes mellitus.Stroke is one of the leading causes of disability and death worldwide.1 The burden of stroke is projected to increase considerably in the next decades. Hence, there is a need to develop effective prevention strategies for stroke, which necessitates a better understanding of the underlying risk factors. About 80% of all strokes are ischemic, 1 but this term describes a syndrome caused by a number of different pathologies, which may have different treatments.2 The major etiologies of ischemic stroke are large artery atherosclerosis (large artery stroke), small vessel atherosclerosis (small vessel stroke), and cardioembolism (cardioembolic stroke). Recent data from genomewide association studies (GWAS) have shown that these subtypes have distinctive risk factor profiles and, by implication, diverse pathophysiologic bases. Type 2 diabetes mellitus (T2D) is associated with an increased risk of ischemic stroke, 4 but its relative contribution to different ischemic stroke subtypes is unknown. Moreover, several risk factors t...

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Section: Discussionmentioning

confidence: 99%

Type 2 diabetes, glucose, insulin, BMI, and ischemic stroke subtypes

Larsson¹,

Scott²,

Traylor³

et al. 2017

Neurology

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“…This approach has identified more than a thousand novel associations with risk of complex diseases including stroke,53 as well as pharmacogenomic effects on the risk of bleeding in patients receiving anticoagulants or antiplatelet agents 54. Screening for these genetic variants in patients with acute stroke is currently too time consuming to be practical prethrombolysis, though specific point-of-care genetic testing may be possible in the future.…”

Section: General Molecular Mechanisms Of Thrombolysismentioning

confidence: 99%

What causes intracerebral bleeding after thrombolysis for acute ischaemic stroke? Recent insights into mechanisms and potential biomarkers

Karaszewski

Houlden

Smith

et al. 2015

J Neurol Neurosurg Psychiatry

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The overall population benefit of intravascular recombinant tissue plasminogen activator (rtPA) on functional outcome in ischaemic stroke is clear, but there are some treated patients who are harmed by early symptomatic intracranial haemorrhage (ICH). Although several clinical and radiological factors increase the risk of rtPA-related ICH, none of the currently available risk prediction tools are yet useful for practical clinical decision-making, probably reflecting our limited understanding of the underlying mechanisms. Finding new methods to identify patients at highest risk of rtPA-related ICH, or new measures to limit risk, are urgent challenges in acute stroke therapy research. In this article, we focus on the potential underlying mechanisms of rtPA-related ICH, highlight promising candidate risk biomarkers and suggest future research directions.

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“…Meta-analysis by the METASTROKE collaboration and review of Genome Wide Association Studies (GWAS) for ischaemic stroke found most genetic variant associations were specific to a subtype, suggesting different subtypes have different risk factor profiles and pathophysiological mechanisms (Markus and Bevan, 2014;Traylor et al, 2012).…”

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confidence: 99%