Project description:Background: African Americans (AA) have increased burdens of cardiovascular disease and cancer compared to Caucasian Americans (CA). This study addresses the possibility that genetic differences affecting the biology of the vascular endothelium could be a factor contributing to this health disparity. Methods: From self-identified, healthy, 20-29 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. Analysis used two distinct approaches. Significance Analysis of Microarray, a FDR-based test, identified significant differential expression of single genes. Gene Set Enrichment Analysis examined expression of pre-determined gene sets that survey each of nine biological systems relevant to endothelial cell biology. Results: At the highly stringent threshold of FDR=0, we identified 31 single genes that were differentially expressed, 4 higher and 27 lower 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 more customary, less stringent threshold of FDR<.05. Using the biological systems approach, we identified shear response biology as being significantly altered for AA versus CA. It detected an apparent tonic increase of expression (AA>CA) for 46/157 genes within that system. Conclusions: The most significant single gene changes detected for AA involved genes having substantial, known roles in endothelial biology. Biological systems analysis suggested that 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 both vascular disease (e.g., hypertension and stroke) and cancer (via angiogenesis). The present findings are consistent with our overarching 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 amongst AA. From self-identified, healthy, 20-29 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. Analysis used two distinct approaches. Significance Analysis of Microarray, a FDR-based test, identified significant differential expression of single genes. Gene Set Enrichment Analysis examined expression of pre-determined gene sets that survey each of nine biological systems relevant to endothelial cell biology.

Project description:Background: African Americans (AA) have increased burdens of cardiovascular disease and cancer compared to Caucasian Americans (CA). This study addresses the possibility that genetic differences affecting the biology of the vascular endothelium could be a factor contributing to this health disparity. Methods: From self-identified, healthy, 20-29 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. Analysis used two distinct approaches. Significance Analysis of Microarray, a FDR-based test, identified significant differential expression of single genes. Gene Set Enrichment Analysis examined expression of pre-determined gene sets that survey each of nine biological systems relevant to endothelial cell biology. Results: At the highly stringent threshold of FDR=0, we identified 31 single genes that were differentially expressed, 4 higher and 27 lower 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 more customary, less stringent threshold of FDR<.05. Using the biological systems approach, we identified shear response biology as being significantly altered for AA versus CA. It detected an apparent tonic increase of expression (AA>CA) for 46/157 genes within that system. Conclusions: The most significant single gene changes detected for AA involved genes having substantial, known roles in endothelial biology. Biological systems analysis suggested that 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 both vascular disease (e.g., hypertension and stroke) and cancer (via angiogenesis). The present findings are consistent with our overarching 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 amongst AA.

Project description:BACKGROUND:Health 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). METHODS:From 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. RESULTS:At 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. CONCLUSIONS:Many 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.

Dataset Information

ERR1 and PGC1? associated mitochondrial alterations correlate with pan-cancer disparity in African Americans.

Publications

ERR1 and PGC1α associated mitochondrial alterations correlate with pan-cancer disparity in African Americans.

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