Asthma is the most common chronic disease in industrialized nations, affecting >14 million people in the U.S. alone. Familial aggregation and concordance rates in monozygotic twins have suggested a significant genetic component to asthma. However, elucidating the role of specific genes has been challenging. We have identified a significant linkage to asthma on chromosome 6p21 in families participating in the Collaborative Study on the Genetics of Asthma (CSGA) (Lod = 3.8). We have narrowed this linked region to a <500 kb region, and identified shared haplotypes that are over transmitted to affected children from heterozygous parents. We replicated this finding in an independently ascertained sample of trios. Two haplotypes explained 85% of the original evidence for linkage to this region, and localized the asthma gene to a 200 kb region. This critical region contains five genes and two pseudogenes. In this application we propose to extend our genetic studies to narrow the length of the shared haplotype; to genotype independently ascertained individuals and families with asthma to further narrow the critical region; and to identify the specific variants in these genes that are associated with asthma risk. In addition, we propose to initiate functional and evolutionary studies in one or more of these genes that continue to show statistical evidence of association to asthma in more than one population sample. Lastly, we will develop novel statistical methods for taking into account gene-gene interactions and use these methods to identify a second chromosomal region that interacts with the chromosome 6p-linked susceptibility locus and/or with a common environmental factor to confer asthma risk. Based on the functional characteristics of the genes in this region we anticipate that these studies will identify a novel mechanism for asthma pathogenesis that could lead to improved therapies and a better understanding of the pathophysiology of this common disease.