Despite the enormous advances over the last century in the understanding of, and the ability to therapeutically manipulate, medical biology, both health disparities and the high prevalence of cardiovascular (including cerebrovascular) disease continue to be perplexing, worldwide medical challenges. From a world health perspective,  health disparities are evident comparing continents, countries, regions, and population subgroups defined, for example, by socioeconomic factors or ethnic/racial group. The reasons these exist are legion, but they basically fall into the categories of environment (in the broadest sense) and genetics. So understanding the basis for extant health disparities is (or will be) a goal of health delivery efforts worldwide.
The present study addresses a specific case of health disparity that is particularly amenable to analysis, the higher burden of cardiovascular disease borne by those of African ancestry who reside within the United States. In so doing, we illustrate the feasibility of a novel investigational approach that offers a way to bridge the current gap between the information provided by structural genomics (for example, identification of loci, genes, alleles, haplotypes associated with disease or disease risk) and the actual consequent impact upon cellular biology and disease pathophysiology. Thus, by demonstrating a way to link these two distinct facets of modern medial biology for vascular disease, the present approach may be very useful. For example, it could help tease out the enormously confounding effect of inter-individual epigenetic changes on attempts to associate a locus with a disease phenotype.
Worldwide, coronary and cerebrovascular disease account for approximately 20% of deaths, an estimated 7.2 and 5.7 million people annually, and they are the two most common causes of death in high- and middle-income countries . This proportion rises to approximately 30% if all cardiovascular disease types (for example, hypertension) are included. Even in low-income countries, cardiovascular disease is exceeded as the cause of death only by infectious diseases (in particular malaria, diarrheal diseases, tuberculosis and HIV) .
Within the United States there are significant health disparities between African Americans (AA) and Caucasian Americans (CA). Notably, AA have a 2.4-fold higher incidence of stroke  and an approximately 50% increase in prevalence of hypertension, the latter affecting approximately 31% of AA [3, 4]. This same disparity exists in the United Kingdom , and a local study verifies that it occurs in our own region from which the present study subjects were drawn . In addition, AA display an increased prevalence of cardiovascular co-morbidities that contribute to pathogenesis in the general population . For example, obesity has a 50% higher prevalence and affects approximately 45% of AA . Correspondingly, AA have a two- to three-fold higher prevalence of type-2 diabetes so that it affects approximately 12% of AA , and they have an increased incidence of smoking, physical inactivity, and peripheral artery disease . In addition to bearing the burden of a higher prevalence of cardiovascular and cerebrovascular disease, AA tend to develop such clinical diseases at a younger age than do CA (see Discussion). Disparities in cancer are addressed in the Discussion.
The debate as to what relative degree environment versus genetics causes these disparities is ongoing and vigorous.
The many factors interposed between racial identification (see Discussion) and any health issue provide a perplexing spectrum of possible non-genetic routes to disease disparity . Examples include nutrition and exposures, access to health care and disparities in its delivery, social conditions and lifestyle choices, and so on. For cardiovascular health, it is telling that urbanization and its accompanying adoption of Western lifestyles are implicated in the accelerating development of hypertension and its comorbidities within Africa . Likewise, the African diaspora established parallel gradients of hypertension and comorbid risk factors from West Africa to the Caribbean to North America [13, 14]. Even within the United States itself there are notable regional differences in stroke mortality rate among AA . Thus, the tremendous influence of environmental factors is indisputable.
The present study, however, was conducted considering the possibility that the exaggerated burden among AA of cardiovascular disease, and perhaps even that of cancer, could stem in part from genetic determinants. Indeed, historical genetic studies indicated that ancestral continent-of-origin can be genetically identified . Application of modern methods (for example, identification of single nucleotide polymorphisms [SNPs], haplotypes, copy-number variable loci, genetic diversity, frequency of non-beneficial SNPs) confirm an East African origin for modern humans with the spread of the human genome to the rest of the world [17–19]. In turn, modern populations can carry genes that confer altered risk (higher or lower) for disease burden . Indeed, newer methods such as discovery of disease association through admixture mapping have implicated specific loci influencing, for example, hypertension [21, 22], blood lipid levels , obesity and type-2 diabetes . Such studies of AA versus CA have been extremely helpful in identifying the relationship between such loci and continent-of-origin.
Environmental and genetic influences do not occur independently; rather, gene-environment interactions contribute to disease variation . Dramatic examples of this in Africa include the sickle mutation, the Duffy mutation, and APOL1 variants conferring protection against P. falciparum, and P. vivax, and Trypanosoma disease, respectively. On the other hand, gene variants that are hypothesized to have been of benefit in ancestral Africa can exert a harmful effect in modern societies. For example, a CYP3A5 allele which may have been advantageous in hot ancestral regions is now associated with salt-sensitivity hypertension in modern AA . Another example is, in principle, found in the "thrifty gene" theory which posits that maximized calorie storage was advantageous ancestrally, but under modern conditions of more abundant food availability, obesity and type-2 diabetes (insulin resistance) are epidemic problems .
Thus, obesity is substantially influenced by genetics and is now understood to be a polygenic, complex disease with very significant gene-environment interaction . Likewise, the relevance of gene-environment interactions has been emphasized for hypertension , stroke , cardiovascular disease , as well as metabolic syndrome, diabetes and atherosclerosis . Furthermore, sequence-independent examples of this have been proposed whereby environmental influences exerted during development, for example, by poor prenatal nutrition, could establish durable, even trans-generational, effects on disease risk among AA through epigenetic mechanisms . At the least, it seems likely that such effects exerted in childhood can cause a child to embark on the road to eventual cardiovascular disease .
The endothelial cell
The vascular endothelial cell is a universal participant in vascular diseases, and for that matter in many "non-vascular" diseases, for example, immune and infectious inflammatory diseases. Therefore, the endothelial cell could be an executor in fulfilment of any potential influence of genomic effects relevant to health discrepancies. Indeed, the endothelial cell is unique in being a critical participant in, and regulator of, multiple vascular functions, as well as comprising the major biological linkage between them. Examples include inflammation biology, governance of the pro- versus anti-coagulant balance, and regulation of vascular tone, among others. These processes and their proximate regulatory mechanisms interact in complex ways, so the functional/physiologic impact of even a precisely known allelic association is not necessarily accurately predictable. Hence, verification of genomic implications on cell biology is of vital importance for understanding pathophysiology, and such information can reveal therapeutic options and even inform pharmaceutical development.
Regarding vascular disease, AA exhibit a variety of findings consistent with endothelial dysfunction, in particular abnormal nitric oxide(NO)-dependent vasorelaxation [33, 34]. Consistent with this, ethnicity affects prevalence of clinically relevant variants of endothelial nitric oxide synthase (eNOS) . Also, cultured umbilical cord endothelial cells from AA babies revealed hints of eNOS malfunction (uncoupling) .
The present study reflects our overarching interest in the concept that genetically-influenced, inter-individual differences in endothelial cell biology contribute to the heterogeneity of clinical phenotype evident in vascular diseases. As a general concept relating genomics and health, this is an accepted and compelling model for complex diseases. Regarding endothelial biology specifically, we previously employed the present approach to reveal gene expression differences coincident with a corresponding exaggerated endothelial cell response to inflammation signaling among the subgroup of children with sickle cell anemia who develop arterial occlusive disease in the Circle of Willis at the base of the brain . Similarly, the present study was enabled by the technology we previously devised  that allows production of robust cultures of reporter endothelial cells (BOEC, blood outgrowth endothelial cells) from peripheral blood obtained from specific, phenotypically-defined individuals, in the present case, those self-identified by race as being AA or CA. We chose this device for subject group assignment because it was the method used for seminal epidemiologic studies of stroke and hypertension prevalence among AA [2, 3], and we wished the present results to be directly relevant to such studies. Caveats regarding this approach for subject group assignment, as well as the very concept of race, are presented in the Discussion.