Asthma is a complex disease in which the interplay between genetic factors and environmental exposures has significant influence on susceptibility and disease prognosis. Asthma is an epidemic that disproportionately affects children and underserved minorities and confers a substantial public health burden, affecting over 20 million Americans. Asthmatics of African descent have more severe asthma than whites, but relatively few studies have focused on this vulnerable racial group. For more than a decade our group has contributed to the effort to identify asthma susceptibility genes in non-white populations. We propose to expand our efforts and simultaneously perform a genome-wide association (GWA) study for asthma and associated quantitative traits in a family-based, African Caribbean population in Barbados (N=1,000), and an independent population of African American asthmatics and non-asthmatics (N=1,000) recruited from the Baltimore-Washington, D.C. metropolitan area, in collaboration with colleagues at Howard University, comprising the consortium on 'Genomic Research on Asthma in the African Diaspora'. A major strength of our application is the collaborative effort with colleagues at the National Heart & Lung Institute in London, who are conducting a GWA study on asthma in panels of English families (N=3,000), which are part of the European Community-based, GABRIEL consortium aiming to identify important genetic and environmental influences on risk of asthma (N=40,000). We will evaluate the generalizability of our findings in the larger U.S. population with colleagues directing the Yale University-sponsored PRAM study of pediatric asthma (N=660 cases and controls). Goals of this study are: (1) to simultaneously perform GWA studies in the family-based and case-control panels of African descent using a genome-wide array of 550,000 SNP markers, with asthma as the primary outcome phenotype in addition to quantitative phenotypes associated with risk of asthma; (2) to cross-validate significant associations using existing data on 400K SNPs from the European consortium, and replicate associations in a separate European American case-control population; and (3) to perform exploratory analyses for gene-gene and gene-environment interactions, with a focus on domestic endotoxin exposure. Findings from this study will provide a better understanding of the complex pathways related to risk of asthma and associated phenotypes. ? ? ?
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