Identification of an Asthma Susceptibility Gene on 3P

BACKGROUND: Asthma is an increasingly common disease caused by bronchial inflammation and characterized by bronchial hyperresponsiveness and intermittent airways obstruction. The development of asthma is most likely determined by an interaction between host susceptibility and environmental exposures. Bronchial hyperresponsiveness (BHR) and elevated total serum IgE levels, characteristic findings in asthma, have been shown to have strong genetic components. The identification of the genetic factors that regulate susceptibility to asthma has important public health consequences, and may lead to an improved understanding of the pathogenesis of asthma. This may lead to improved preventive measures and new therapeutic approaches. The study is in response to a Request for Applications on "Positional Candidate Gene Approaches in Asthma Gene Discovery" issued in October 1999. DESIGN NARRATIVE: In an effort to delineate genetic susceptibility to asthma, Dr. Bleecker and colleagues have identified several regions of the genome that contain potential asthma susceptibility genes using a Dutch population of 200 families ascertained through a proband with asthma. The two regions with the strongest evidence for linkage after completing a genome screen were located on chromosomes 3p14-p21 and 5q31. They will identify the asthma susceptibility gene located on chromosome 3p using the Dutch families and determine its contribution to this disease in other populations. There are six specific aims in the study. The first is to develop a high-resolution genetic map of the candidate region on chromosome 3p14-p21. The second aim is to construct a correlated genetic and physical map of the candidate region on chromosome 3p. The third aim is to genotype an additional cohort of Dutch trios (one affected child and both parents) to identify haplotypes and to confirm case-control candidate gene studies. The fourth aim is to analyze known and novel genes from the candidate region using a case-control study design in the same population. The fifth aim is to determine the contribution of the chromosome 3p asthma susceptibility gene in other populations including the U.S. Collaborative Study for the Genetics of Asthma (CSGA) and Dr. Ober's Hutterite population. The sixth aim is to characterize the identified single nucleotide polymorphism (SNP) or haplotype that contributes to asthma susceptibility. There will be interaction with other investigators to determine the impact of each genetic locus and to investigate gene-gene interactions.