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 (SNP) on chromosome 7p21.1 and large vessel ischaemic 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 SNPs were associated with asymptomatic carotid plaque (N=25179) and carotid intima-media thickness (N=31210) 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 SNPs (rs11984041 and rs2107595) were associated with common carotid IMT (rs2107595 p=0.0018) and with presence of carotid plaque (rs2107595 p=0.0022). In both cerebral and systemic arteries, HDAC9 labelling was seen in nuclei and cytoplasm of vascular smooth muscle cells, and in endothelial cells. HDAC9 expression was upregulated in carotid plaques compared to left internal thoracic controls (p=0.00000103). It was also up-regulated in aortic and femoral plaques compared to 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.

Role of histone deacetylase 9 in regulating adipogenic differentiation and high fat diet-induced metabolic disease

“…In addition, HDAC9 is expressed in vascular cells and tissues. 49 Elevated vascular HDAC9 expression was reported to be associated with aortic and femoral atherosclerosis as well as carotid artery disease and large vessel ischemic stroke in humans. 49 Moreover, a recent genome-wide association study found two single nucleotide polymorphic (SNP) variants of HDAC9 to be strongly linked to large blood vessel disease in humans.…”

“…49 Elevated vascular HDAC9 expression was reported to be associated with aortic and femoral atherosclerosis as well as carotid artery disease and large vessel ischemic stroke in humans. 49 Moreover, a recent genome-wide association study found two single nucleotide polymorphic (SNP) variants of HDAC9 to be strongly linked to large blood vessel disease in humans. 50 These findings raise the intriguing possibility that therapeutically targeting HDAC9 in obesity could also favorably modulate the development of cardiovascular complications, a major cause of morbidity and mortality in this population.…”

Wellcome Trust Genome-Wide Association Study of Ischemic Stroke

“…13 However, an effect via increasing neuronal survival might also be expected to increase risk for stroke caused by cardiac embolism as well as large artery embolism, and there was no evidence of any association between the 7p21.1 locus and cardioembolic stroke. Initial studies 14 in our laboratory have shown that HDAC9 is expressed in both intracranial and systemic large arteries, including carotid and coronary arteries. Abundant staining was found both in the endothelium and smooth muscle cells.…”

Mechanisms and treatment of ischaemic stroke—insights from genetic associations

“…39 Levels of HDAC9 mRNA expression were found to be elevated above normal levels in carotid athero sclerotic plaques compared with non diseased arterial wall. 38 Interestingly, this elevation was seen to a greater degree in carotid plaques than in athero sclerotic plaques elsewhere in the body. The reasons for this difference are unknown, although the HDAC9 variant was recently associated with coronary artery disease, 40 and it is of interest that this association was weaker than the association with large-artery stroke.…”