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-1/tumor necrosis factor␣. 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. IntroductionMany human diseases present in a clinically variable manner, yet the basis for the biologic phenomenon of phenotypic heterogeneity, the variation in presentation of any given disease, is generally unknown. We have used a specific example of this phenomenon to address our overarching hypothesis that genetic, inherited differences in endothelial biology can underlie the phenotypic heterogeneity of human vascular disease.Sickle cell anemia, caused by inherited homozygosity for the mutant sickle hemoglobin, is a disease characterized by anemia, vascular occlusions, and chronic organ damage. It has an exceedingly complex pathophysiology and incredibly diverse clinical complications. 1 Among these, there are 3 stroke syndromes: clinically silent strokes occurring in children resulting from multifocal small vessel disease; hemorrhagic strokes occurring in adults; and clinical ischemic stroke, the classical stroke syndrome of sickle cell anemia.Notably, approximately 10% of children with sickle cell anemia develop classic ischemic stroke, with peak age being approximately 5 years. 2,3 Risk factors include elevated white count, low blood hemoglobin, hypertension, and a prior neurologic event. [2][3][4][5] However, the primary risk factor is occlusive disease at the circle of Willis (CoW), 6,7 the encircling structure of medium to large vessels at the base of the brain. CoW disease is thought to be causal, as the strokes tend to be due to thrombosis occurring over the area of vessel wall abnormality, and the extent of stroke correlates with degree of CoW stenosis. 2,8 Stroke pathogenesis does not simply involve sickling in the vasa vasorum because vessels in the CoW do not have vasa vasorum. 9 Our hypothesis ...
BackgroundHealth disparities and the high prevalence of cardiovascular disease continue to be perplexing worldwide health challenges. This study addresses the possibility that genetic differences affecting the biology of the vascular endothelium could be a factor contributing to the increased burden of cardiovascular disease and cancer among African Americans (AA) compared to Caucasian Americans (CA).MethodsFrom self-identified, healthy, 20 to 29-year-old AA (n = 21) and CA (n = 17), we established cultures of blood outgrowth endothelial cells (BOEC) and applied microarray profiling. BOEC have never been exposed to in vivo influences, and their gene expression reflects culture conditions (meticulously controlled) and donor genetics. Significance Analysis of Microarray identified differential expression of single genes. Gene Set Enrichment Analysis examined expression of pre-determined gene sets that survey nine biological systems relevant to endothelial biology.ResultsAt the highly stringent threshold of False Discovery Rate (FDR) = 0, 31 single genes were differentially expressed in AA. PSPH exhibited the greatest fold-change (AA > CA), but this was entirely accounted for by a homolog (PSPHL) hidden within the PSPH probe set. Among other significantly different genes were: for AA > CA, SOS1, AMFR, FGFR3; and for AA < CA, ARVCF, BIN3, EIF4B. Many more (221 transcripts for 204 genes) were differentially expressed at the less stringent threshold of FDR <.05. Using the biological systems approach, we identified shear response biology as being significantly different for AA versus CA, showing an apparent tonic increase of expression (AA > CA) for 46/157 genes within that system.ConclusionsMany of the genes implicated here have substantial roles in endothelial biology. Shear stress response, a critical regulator of endothelial function and vascular homeostasis, may be different between AA and CA. These results potentially have direct implications for the role of endothelial cells in vascular disease (hypertension, stroke) and cancer (via angiogenesis). Also, they are consistent with our over-arching hypothesis that genetic influences stemming from ancestral continent-of-origin could impact upon endothelial cell biology and thereby contribute to disparity of vascular-related disease burden among AA. The method used here could be productively employed to bridge the gap between information from structural genomics (for example, disease association) and cell function and pathophysiology.
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