title: Evidence HDAC9 genetic variant associated with ischemic stroke increases risk via promoting carotid atherosclerosis.
abstract: OBJECTIVE
  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.
authors: Stroke and Dementia Research Centre, St George's University of London, London SW19 3QZ, United Kingdom. hmarkus@sgul.ac.uk
authors: Hugh S
authors: HS
authors: Markus
authors: Kari-Matti
authors: KM
authors: Mäkelä
authors: Steve
authors: S
authors: Bevan
authors: Emma
authors: E
authors: Raitoharju
authors: Niku
authors: N
authors: Oksala
authors: Joshua C
authors: JC
authors: Bis
authors: Chris
authors: C
authors: O'Donnell
authors: Atticus
authors: A
authors: Hainsworth
authors: Terho
authors: T
authors: Lehtimäki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001011:Aorta / Q000000981:diagnostic imaging; D050197:Atherosclerosis / Q000000981:diagnostic imaging / Q000235:genetics; D002545:Brain Ischemia / Q000235:genetics*; D002339:Carotid Arteries / Q000000981:diagnostic imaging; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000235:genetics; D059168:Carotid Intima-Media Thickness; D005260:Female; D020022:Genetic Predisposition to Disease; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D012307:Risk Factors; D020521:Stroke / Q000000981:diagnostic imaging / Q000235:genetics*
chemical_list: D012097:Repressor Proteins; C486544:HDAC9 protein, human; D006655:Histone Deacetylases