Genetic endothelial systems biology of sickle stroke risk. Blood 2008 Apr 01;111(7):3872-9
Date
12/25/2007Pubmed ID
18156497Pubmed Central ID
PMC2275038DOI
10.1182/blood-2007-06-097188Scopus ID
2-s2.0-43549114344 (requires institutional sign-in at Scopus site) 51 CitationsAbstract
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 RelA activation on the part of blood outgrowth endothelial cells from the at-risk subjects in response to stimulation with interleukin-1beta/tumor necrosis factoralpha. 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.
Author List
Chang Milbauer L, Wei P, Enenstein J, Jiang A, Hillery CA, Scott JP, Nelson SC, Bodempudi V, Topper JN, Yang RB, Hirsch B, Pan W, Hebbel RPMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Anemia, Sickle Cell
Cells, Cultured
Child
Child, Preschool
Circle of Willis
Endothelial Cells
Endothelium, Vascular
Female
Gene Expression Profiling
Gene Expression Regulation
Humans
Inflammation
Interleukin-1beta
Male
Risk Factors
Signal Transduction
Stroke
Transcription Factor RelA
Tumor Necrosis Factor-alpha
