(Applicant?s Abstract) Asthma is a major public health problem. Cumulating evidence suggests that genetic factors are essential determinants of both the development and severity of asthma. Family-based association studies, utilizing statistical methods such as the transmission disequilibrium test, provide the best opportunity of identifying the relationship of positional candidate genes to asthma phenotypes. The Childhood Asthma Management Program (CAMP) is a large and successful clinical trial of 1041 asthmatic children initially aged five to twelve. This valuable data set includes 678 complete parent/child trios and 246 parent/child pairs which can be utilized for family-based association studies on asthma positional candidates. We have demonstrated linkage to asthma and total serum IgE to markers on chromosome l2q13-24 in the CAMP population. This region has also been demonstrated to be linked to asthma phenotypes in whole genome scans and more limited linkage studies in other populations. The region contains numerous interesting positional candidate genes for asthma including: neural NO synthase (NOS 1), interferon-gamma (IFN-gamma), leukotriene a-4 hydrolase (LTA4H), STAT6, beta subunit of nuclear factor-Y (NFYB), mast cell growth factor (MGF), and insulin-like growth factor 1 (IGF-1). A variable pattern of linkage disequilibriurn between nearby genetic loci necessitates the identification of multiple SNPs within a positional candidate gene, in order to avoid falsely excluding the candidate gene. Family-based association methods will be used with individual SNPs, and with haplotypes of adjacent SNPs, to narrow regions likely to contain susceptibility genes and to test variants within the positional candidate genes to identify genetic determinants of asthma, atopy, and asthma severity. Family-based association analyses will be performed with asthma and atopy related phenotypes including: physician diagnosed asthma, allergic rhinitis, airway responsiveness, bronchodilator response, skin test reactivity, peripheral blood eosinophil count, total and specific IgE levels, using SNPs identified within positional candidate genes to narrow the chromosome l2q13-24, region likely to contain genetic influences on the development of asthma and atopy. Similar analyses will be performed with asthma severity phenotypes including age of onset of asthma, spirometry, peak flow variability, frequency of asthma exacerbations, hospitalizations and emergency room visits, and requirement for systemic corticosteroid treatment to determine if the chromosome l2q13-24 positional candidate gene SNPs include genetic influences on the severity of asthma. Finally, genotype by environment interactions will be assessed between environmental exposures (determined by questionnaire), passive smoking, furry pets, and house dust antigen measurements and SNP markers within chromosome l2q13-24 positional candidate genes on phenotypes related to asthma severity.
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