TY - JOUR
T1 - Genetic endothelial systems biology of sickle stroke risk
AU - Milbauer, Liming Chang
AU - Wei, Peng
AU - Enenstein, Judy
AU - Jiang, Aixiang
AU - Hillery, Cheryl A.
AU - Scott, J. Paul
AU - Nelson, Stephen C.
AU - Bodempudi, Vidya
AU - Topper, James N.
AU - Yang, Ruey Bing
AU - Hirsch, Betsy
AU - Pan, Wei
AU - Hebbel, Robert P.
PY - 2008/4/1
Y1 - 2008/4/1
N2 - Genetic differences in endothelial biology could underlie development of pheno- typic 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)ornot-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 signifi-cant 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 RelA activation on the part of blood outgrowth endothelial cells from the at-risk subjects in response to stimulation with interleukin-1β/tumor necrosis factorα. We conclude that the pathobiol-ogy 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.
AB - Genetic differences in endothelial biology could underlie development of pheno- typic 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)ornot-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 signifi-cant 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 RelA activation on the part of blood outgrowth endothelial cells from the at-risk subjects in response to stimulation with interleukin-1β/tumor necrosis factorα. We conclude that the pathobiol-ogy 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.
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U2 - 10.1182/blood-2007-06-097188
DO - 10.1182/blood-2007-06-097188
M3 - Article
C2 - 18156497
AN - SCOPUS:43549114344
SN - 0006-4971
VL - 111
SP - 3872
EP - 3879
JO - Blood
JF - Blood
IS - 7
ER -