Genetic endothelial systems biology of sickle stroke risk
Genetic endothelial systems biology of sickle stroke risk
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DOI：
10.1182/blood-2007-06-097188
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发表时间：
2008-04-01
期刊：
影响因子：
20.3
通讯作者：
Hebbel, Robert P.
中科院分区：
文献类型：
--
作者：
Milbauer, Liming Chang;Wei, Peng;Hebbel, Robert P.
内皮生物学的遗传差异可能是血管疾病患者表型异质性发展的基础。我们从20名镰状细胞性贫血患者（年龄4-19岁）中获得了血液外生内皮细胞，这些患者分别因威利斯肌圈有或没有闭塞性疾病而有缺血性卒中风险（n = 11）或无风险（n = 9）。正如预期的那样，基因表达谱在两组之间没有发现显著的单基因差异。然而，生物系统评分分析，使用预先确定的基因集来调查9个生物系统中的每一个，表明只有炎症信号的变化是高危受试者的特征，这得到了多种统计方法的支持。相应的，随后的生物学测试显示，在受到介素-1 /肿瘤坏死因子α刺激的情况下，高危受试者的血液外生内皮细胞的ReIA激活明显夸大。我们的结论是，镰状细胞性贫血儿童的威利斯环病的病理生物学主要涉及炎症生物学，这可能反映了遗传决定的内皮生物学的差异，这些差异解释了不同的宿主对炎症的反应。
Genetic differences in endothelial biology could underlie development of phenotypic heterogeneity among persons afflicted with vascular diseases. We obtained blood outgrowth endothelial cells from 20 subjects with sickle cell anemia (age, 4-19 years) shown to be either at-risk (n = 11) or not-at-risk (n = 9) for ischemic stroke because of, respectively, having or not having occlusive disease at the circle of Willis. Gene expression profiling identified no significant single gene differences between the 2 groups, as expected. However, analysis of Biological Systems Scores, using gene sets that were predetermined to survey each of 9 biologic systems, showed that only changes in inflammation signaling are characteristic of the at-risk subjects, as supported by multiple statistical approaches. Correspondingly, subsequent biologic testing showed significantly exaggerated ReIA activation on the part of blood outgrowth endothelial cells from the at-risk subjects in response to stimulation with interieukin-1 beta/tumor necrosis factor alpha. We conclude that the pathobiology of circle of Willis disease in the child with sickle cell anemia predominantly involves inflammation biology, which could reflect differences in genetically determined endothelial biology that account for differing host responses to inflammation.