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Evidence HDAC9 genetic variant associated with ischemic stroke increases risk via promoting carotid atherosclerosis.

ABSTRACT: BACKGROUND AND PURPOSE:A novel association between a single nucleotide polymorphism on chromosome 7p21.1 and large-vessel ischemic stroke was recently identified. The most likely underlying gene is histone deacetylase 9 (HDAC9). The mechanism by which HDAC9 increases stroke risk is not clear; both vascular and neuronal mechanisms have been proposed. METHODS:We determined whether the lead single nucleotide polymorphisms were associated with asymptomatic carotid plaque (N=25 179) and carotid intima-media thickness (N=31 210) detected by carotid ultrasound in a meta-analysis of population-based and community cohorts. Immunohistochemistry was used to determine whether HDAC9 was expressed in healthy human cerebral and systemic arteries. In the Tampere Vascular Study, we determined whether HDAC9 mRNA expression was altered in carotid (N=29), abdominal aortic (N=15), and femoral (N=24) atherosclerotic plaques compared with control (left internal thoracic, N=28) arteries. RESULTS:Both single nucleotide polymorphisms (rs11984041 and rs2107595) were associated with common carotid intima-media thickness (rs2107595; P=0.0018) and with presence of carotid plaque (rs2107595; P=0.0022). In both cerebral and systemic arteries, HDAC9 labeling was seen in nuclei and cytoplasm of vascular smooth muscle cells, and in endothelial cells. HDAC9 expression was upregulated in carotid plaques compared with left internal thoracic controls (P=0.00000103). It was also upregulated in aortic and femoral plaques compared with controls, with mRNA expression increased in carotid compared with femoral plaques (P=0.0038). CONCLUSIONS:Our results are consistent with the 7p21.1 association acting via promoting atherosclerosis, and consistent with alterations in HDAC9 expression mediating this increased risk. Further studies in experimental models are required to confirm this link.

SUBMITTER: Markus HS

PROVIDER: S-EPMC4206941 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Evidence HDAC9 genetic variant associated with ischemic stroke increases risk via promoting carotid atherosclerosis.

Markus Hugh S HS Mäkelä Kari-Matti KM Bevan Steve S Raitoharju Emma E Oksala Niku N Bis Joshua C JC O'Donnell Chris C Hainsworth Atticus A Lehtimäki Terho T

Stroke 20130228 5

<h4>Background and purpose</h4>A novel association between a single nucleotide polymorphism on chromosome 7p21.1 and large-vessel ischemic stroke was recently identified. The most likely underlying gene is histone deacetylase 9 (HDAC9). The mechanism by which HDAC9 increases stroke risk is not clear; both vascular and neuronal mechanisms have been proposed.<h4>Methods</h4>We determined whether the lead single nucleotide polymorphisms were associated with asymptomatic carotid plaque (N=25 179) an ...[more]

PMID: 23449258

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Project description:ImportanceA better understanding of the role of atherosclerosis in the development of ischemic stroke subtypes could help to improve strategies for prevention of stroke worldwide.ObjectiveTo assess the role of carotid atherosclerosis in the association between major cardiovascular risk factors and ischemic stroke subtypes.Design, setting, and participantsThe prospective China Kadoorie Biobank cohort study was conducted in the general population of 5 urban and 5 rural areas in China, with a baseline survey obtained between June 2004 and July 2008. A random sample of 23 973 participants with no history of cardiovascular disease at enrollment who had carotid artery ultrasonographic measurements recorded at a resurvey from September 2013 to June 2014 were included. Data analysis was performed from July 1, 2016, to April 10, 2019.ExposuresMajor cardiovascular risk factors (ie, blood pressure [BP], blood lipid levels, smoking, and diabetes).Main outcomes and measuresCarotid ultrasonographic measures of plaque burden (derived from number and maximum size of carotid artery plaques at resurvey) and first ischemic stroke during follow-up (n = 952), with subtyping (data release, August 2018) as lacunar (n = 263), probable large artery (n = 193), probable cardioembolic (n = 66), or unconfirmed (n = 430). Associations between cardiovascular risk factors, carotid plaque burden, and ischemic stroke subtypes were adjusted for age, sex, and geographic area.ResultsThe 23 973 participants in the study had a mean (SD) age of 50.6 (10.0) years, and 14 833 (61.9%) were women. Systolic BP had a stronger association (odds ratio [OR] per SD, 1.51; 95% CI, 1.42-1.61) than plaque burden (OR per SD, 1.34; 95% CI, 1.26-1.44) with ischemic stroke, and the associations of systolic BP with each subtype of ischemic stroke were modestly attenuated by adjustment for plaque burden. After adjustment for BP, plaque burden had a stronger association with probable large artery stroke (OR, 1.43; 95% CI, 1.24-1.63) than with lacunar stroke (OR, 1.25; 95% CI, 1.10-1.43) but was not associated with probable cardioembolic stroke (OR, 1.06; 95% CI, 0.83-1.36).Conclusions and relevanceAlthough BP was an important risk factor for all ischemic stroke subtypes, carotid atherosclerosis was an important risk factor only for large artery and lacunar strokes, suggesting that drug treatments targeting atherosclerosis may reduce the risk of stroke subtypes to different extents.

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Evidence HDAC9 genetic variant associated with ischemic stroke increases risk via promoting carotid atherosclerosis.

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Evidence HDAC9 genetic variant associated with ischemic stroke increases risk via promoting carotid atherosclerosis.

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