Asthma affects more than 17 million people in the United States and African-Americans are significantly more likely than Caucasians to be diagnosed with asthma. Alarmingly, asthma-related hospitalization and mortality in African Americans are also high. Key environmental factors, particularly those found indoors which have been shown to have relevance to pathogenesis of asthma, include allergens such as cockroach (Bla g 1) and airborne particulate matter (PM). These exposures are especially common in urban environments, where many affected African-Americans reside. Twin studies and studies of first-degree relatives of asthmatic individuals, that were not restricted to African-Americans, indicate a genetic component in the risk for asthma. Evidence supports the hypothesis that key genes may reside on chromosomes 5q, 12q and 17q but little is known about allelic variants of these candidate asthma genes in African Americans. The proposed study will examine the genetic basis of asthma in African-Americans with specific attention to genetic modifiers involved in the enhanced susceptibility of certain patients to airborne particulate matter and antigens. Our strategy is to employ high-throughput genomic technologies to examine the (i) patterns of gene expression to identify candidate genes and (ii) the genetic basis for polymorphisms in genes which explain susceptibility to PM in an inner city African-American population with asthma. Vital assets in this work include the tremendous efficiencies gained from working with populations of 900 African-American subjects who have been, or will be, recruited by studies funded separately, including approximately 400 subjects from the NIEHS/EPA funded Center for Childhood Asthma in the Urban Environment and 624 subjects from the Baltimore Asthma Severity Study (BASS) study. Other key resources that provide substantial leverage of resources, include the Microarray facilities and Genotyping cores that are resources of the NHLBI-funded Programs for Genomics Applications (PI: Garcia), including sharing of costs of microarray chips and supplies. The following specific aims are supported by the proposed study:
Aim #1. To obtain and prioritize candidate genes for susceptibility to airborne particulate matter through gene expression profiling in human CD4+ T-lymphocytes.
Aim #2. To identify polymorphisms in candidate genes associated with susceptibility to PM exposure in asthma and with asthma severity.
Aim #3. To identify polymorphisms in candidate genes associated with an interactive effect of cockroach allergen and PM10 exposures on asthma severity.
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