Epidemiologic data indicate that a major risk factor for asthma is a positive family history. However, genes that confer susceptibility to asthma are unknown. We propose to identify asthma susceptibility loci by performing two-point and complex linkage analysis with microsatellite markers distributed throughout the genome in families with well-defined asthma. Our study will focus on two distinct samples: Chicago inner-city and suburban families ascertained through the pediatric and adult asthma clinics at the University of Chicago and members of the Hutterite brethren, a religious isolate that lives on communal farms in South Dakota. The latter population has previously been characterized with respect to asthma and other respiratory illnesses. We propose to study 150 clinic families (average family size = 10) and eight multigenerational Hutterite families. Families will be selected through asthmatic probands who have at least one first degree relative with asthma. The diagnosis of asthma in affected and unaffected subjects will be made using strict criteria based on medical history and results of spirometry and methacholine challenge studies. Skin tests for commonly inhaled antigens will be performed, and IgE levels and eosinophil counts will be measured on all subjects. All family members will be genotype for up to 300 polymorphic DNA markers (microsatellite markers) that map near """"""""candidate susceptibility loci"""""""" or are distributed randomly throughout the genome. Permanent lines will be established or cells derived from all subjects. Preliminary screening of genetic data will be performed using two-point linkage analysis, considering two genetic models that include a disease prevalence of 10 and assume heterogeneity but vary with respect to penetrance and the proportional contribution of the susceptibility locus (20% vs. 40%). A two-point lod score greater than 2.0 under any genetic model will be subjected to further investigation using nonparametric tests, multipoint linkage analysis, and more sophisticated genetic models that incorporate additional genetic and environmental covariates. If linkage to a susceptibility locus is found, attempts will be make to identify and clone the susceptibility locus. Once susceptibility alleles are known, preventive measures can focus on individuals at-risk for developing asthma. Identifying asthma susceptibility alleles would also contribute toward elucidating the primary defect in asthma and advance the development of improved treatments.
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