Fine mapping of an Asthma Locus of Chromosome 12q

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DESCRIPTION (provided by applicant): Bronchial asthma affects over 17 million people in the United States and continues to be a significant cause of morbidity in the U.S. There is substantial evidence that asthma is a complex genetic disorder, and there is hope that identification of the genetic determinants of asthma will lead to a better understanding of asthma pathobiology and potentially lead to the development of new preventative strategies and treatment regimens. Towards this end, many groups around the world have performed genome-wide linkage scans in an attempt to identify regions conferring heightened asthma-susceptibility. The centromeric region of chromosome 12q is one of the most frequently identified regions demonstrating evidence for linkage with asthma (in 6 of 11 published studies). We hypothesize that an asthma-susceptibility gene exists on chromosome 12q, and that this gene can be identified using a high-resolution single nucleotide polymorphism (SNP) mapping strategy. We propose a three-stage plan to identify this locus. In stage 1, we will screen approximately 1,500 SNPs in two samples of pooled DNA: one DNA pool from 394 asthmatics identified in the Nurses Health Study (NHS) and one pool of matched healthy controls. We will screen for evidence of significant allele-frequency differences between the case and control pools and identify SNPs that are associated with the asthma phenotype ("positive-SNPs"). In stage 2, we will validate our findings from stage 1 by genotyping the "positive-SNPs" in the individual DNA samples from the NHS. Genotyping of individual samples will allow for more accurate estimation of allele frequency and to enable explicit case-control association analysis, as well as haplotype imputation. In stage 3, we will replicate findings from the NHS asthma cohort in a family-based cohort of 460 asthmatic offspring and their parents obtained through the Childhood Asthma Management Program (CAMP). CAMP has extensive phenotypic information including assessment of lung function, airways responsiveness and atopy-related traits. We will validate SNPs from stage 2 in 460 asthma trios and perform family-based association analyses using both the asthma phenotype and intermediate quantitative traits. We anticipate identifying SNPs associated with asthma in both the NHS and CAMP cohorts, representing important asthma-susceptibility SNPs. Identification of these variants may have a significant impact on the public health of asthma patients.