Project description:On average, African Americans with multiple sclerosis demonstrate higher inflammatory disease activity, faster disability accumulation, greater visual dysfunction, more pronounced brain tissue damage and higher lesion volume loads compared to Caucasian Americans with multiple sclerosis. Neurodegeneration is an important component of multiple sclerosis, which in part accounts for the clinical heterogeneity of the disease. Brain atrophy appears to be widespread, although it is becoming increasingly recognized that regional substructure atrophy may be of greater clinical relevance. Patient race (within the limitations of self-identified ancestry) is regarded as an important contributing factor. However, there is a paucity of studies examining differences in neurodegeneration and brain substructure volumes over time in African Americans relative to Caucasian American patients. Optical coherence tomography is a non-invasive and reliable tool for measuring structural retinal changes. Recent studies support its utility for tracking neurodegeneration and disease progression in vivo in multiple sclerosis. Relative to Caucasian Americans, African American patients have been found to have greater retinal structural injury in the inner retinal layers. Increased thickness of the inner nuclear layer and the presence of microcystoid macular pathology at baseline predict clinical and radiological inflammatory activity, although whether race plays a role in these changes has not been investigated. Similarly, assessment of outer retinal changes according to race in multiple sclerosis remains incompletely characterized. Twenty-two African Americans and 60 matched Caucasian Americans with multiple sclerosis were evaluated with brain MRI, and 116 African Americans and 116 matched Caucasian Americans with multiple sclerosis were monitored with optical coherence tomography over a mean duration of 4.5 years. Mixed-effects linear regression models were used in statistical analyses. Grey matter (-0.9%/year versus -0.5%: P =0.02), white matter (-0.7%/year versus -0.3%: P =0.04) and nuclear thalamic (-1.5%/year versus -0.7%/year: P =0.02) atrophy rates were approximately twice as fast in African Americans. African Americans also exhibited higher proportions of microcystoid macular pathology (12.1% versus 0.9%, P =0.001). Retinal nerve fibre layer (-1.1% versus -0.8%: P =0.02) and ganglion cell+ inner plexiform layer (-0.7%/year versus -0.4%/year: P =0.01) atrophy rates were faster in African versus Caucasian Americans. African Americans on average exhibited more rapid neurodegeneration than Caucasian Americans and had significantly faster brain and retinal tissue loss. These results corroborate the more rapid clinical progression reported to occur, in general, in African Americans with multiple sclerosis and support the need for future studies involving African Americans in order to identify individual differences in treatment responses in multiple sclerosis.

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: 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.

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Preinvasive Colorectal Lesions of African Americans Display an Immunosuppressive Signature Compared to Caucasian Americans.

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