This proposal seeks to examine the genetic factors that influence the development of asthma in a minority group at high risk for the disease (Hispanics). To this end, we will concentrate on a genetically isolated Hispanic population with high asthma prevalence living in the Central Valley of Costa Rica. To identify regions of the genome likely to contain genetic determinants of asthma and associated phenotypes in this population, we will utilize a unique study design that entails collection of phenotypic and genotypic data on 15 large pedigrees multiplex for asthma (600 individuals) and 300 unrelated asthmatic children and their parents (900 individuals). We will conduct a genome screen on these large pedigrees, and we will perform linkage analysis of asthma and seven intermediate phenotypes related to asthma including airway responsiveness; FEV 1; bronchodilator responsiveness; skin test reactivity to common aeroallergens; serum total and allergen-specific IgE; and peripheral blood eosinophil count. A genome screen will also be conducted in the parent-child trios, and ancestral haplotypes will be reconstructed to identify regions influencing asthma- associated phenotypes. Within candidate regions demonstrating both linkage in extended pedigrees to asthma and/or asthma-related phenotypes and significant linkage disequilibrium within the unrelated asthmatic subjects, fine mapping will be performed by testing for genetic association to single nucleotide polymorphisrns within positional candidate genes. By utilizing a unique study design with a large sample size in a genetically isolated population, we should be able to address an important but insufficiently studied problem: the genetic influences on the expression of the asthma phenotype in Hispanics. Thus, this proposal will greatly contribute to our understanding of the pathogenesis of a significant public health problem among Hispanic Americans: bronchial asthma.
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