Stroke and Dementia Research Centre, St George's University of London, London SW19 3QZ, United Kingdom.
Stroke. 2013 May;44(5):1220-5. doi: 10.1161/STROKEAHA.111.000217. Epub 2013 Feb 28.
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.
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.
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).
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.
最近发现，7p21.1 染色体上的一个单核苷酸多态性与大血管缺血性卒中之间存在新的关联。最有可能的潜在基因是组蛋白去乙酰化酶 9（HDAC9）。HDAC9 增加卒中风险的机制尚不清楚；有人提出了血管和神经元机制。
我们通过对基于人群和社区队列的荟萃分析，确定了主要的单核苷酸多态性是否与颈动脉超声检测到的无症状颈动脉斑块（N=25179）和颈动脉内膜中层厚度（N=31210）有关。免疫组织化学用于确定 HDAC9 是否在健康的人脑和全身动脉中表达。在坦佩雷血管研究中，我们确定了与对照（左内胸动脉，N=28）动脉相比，颈动脉（N=29）、腹主动脉（N=15）和股动脉（N=24）粥样硬化斑块中 HDAC9mRNA 表达是否改变。
rs11984041 和 rs2107595 两种单核苷酸多态性均与颈总动脉内膜中层厚度（rs2107595；P=0.0018）和颈动脉斑块存在相关（rs2107595；P=0.0022）。在脑和全身动脉中，HDAC9 标记物可见于血管平滑肌细胞核和细胞质以及内皮细胞中。与对照相比，颈动脉斑块中 HDAC9 的表达上调（P=0.00000103）。与对照组相比，主动脉和股动脉斑块中 HDAC9 的表达也上调，与股动脉斑块相比，颈动脉斑块中 HDAC9 的 mRNA 表达增加（P=0.0038）。
我们的结果与 7p21.1 关联通过促进动脉粥样硬化而发挥作用的结果一致，与介导这种风险增加的 HDAC9 表达改变的结果一致。需要在实验模型中进一步研究来证实这一联系。
