The recent rise in asthma morbidity and mortality has impacted the African American population disproportionately. It is likely that in addition to environmental exposures, genetic susceptibility factors have contributed to this disparity. Little is known, however, about how specific genetic polymorphisms, including those on chromosome 5q, impact the pathogenesis of asthma. Though the prevalence of specific polymorphisms (allelic variants) is known to vary across populations (population stratification), genetic studies on asthma in African Americans have characteristically included small numbers, and inadequate controls. Moreover, there is almost no information about the immunological pathways that contribute to asthma severity in this population. Our study, DASH (Determinants of Asthma Severity in Harlem), seeks to establish the link between specific genotypic variants and phenotypic markers, and to elucidate immunological pathways that contribute to asthma severity in an African American population. DASH addresses the next step in reaching our long-range goal, i.e., to control asthma in the African American population of Harlem. We propose a case-control study of individuals of African American heritage, who live in Central and West Harlem. We will test our central hypothesis: Polymorphisms in candidate asthma genes on chromosome 5g modify disease severity in individuals who have asthma, and these polymorphisms and specific T cell response phenotypes differ between individuals who have asthma and those who do not. The research plan will address the following specific aims: (1) to define the phenotype and allelic variants of the IL-4, IL-13 and Beta2-adrenoreceptor genes among African American asthmatic individuals (cases) and controls; and (2) to define T cell response phenotypes among African Americans who have asthma. The DASH study represents the largest effort undertaken to date, to study the genetics of asthma in an African American population; and it seeks to elucidate important immunological mechanisms (T-cell responses) that contribute to asthma severity. Moreover, it enables the linkage of T-cell responses to specific allelic variants. Our approach is to apply modern technologies (haplotype analysis; immunophenotyping) toward development of a mechanism-based framework for understanding pathways that underlie asthma severity in the African American population. The data collected through the DASH study will elucidate the relevance of emerging directions for asthma management, including pharmacogenetic strategies, for this population. The potential public health benefits are critical for the asthmatic population in general.
