Asthma Clinical Trial
To conduct molecular genetic studies in human pedigrees in order to identify the major genes responsible for asthma.
BACKGROUND:
Asthma is a respiratory disease characterized by variable airways obstruction, airways
inflammation and bronchial hyperresponsiveness (BHR). There are recent increases in asthma
mortality and prevalence in the US, especially in African-Americans. Multiple studies suggest
that both genetic and environmental factors are important in asthma susceptibility.
The study was recommended by the Pulmonary Diseases Advisory Committee at its February 1991
meeting and given concept approval by the May 1991 National Heart, Lung, and Blood Advisory
Council. The Request for Applications was released in October 1992.
DESIGN NARRATIVE:
The CSGA was composed of five centers (Johns Hopkins University, University of Chicago,
University of Maryland, University of Minnesota, and a data coordinating center at Wake
Forest). At each center, families were ascertained through two siblings with asthma. All
family members were characterized with spirometry, bronchial responsiveness to methacholine
or reversibility testing, skin-tests and questionnaire data. The initial genome screen was
completed on the first 237 sib pairs from three racial groups (African-American, Caucasian
and Hispanic), and genotyping on the remaining family members and families was completed
before the study was renewed in 1997. Therefore, the initial aim of the CSGA to map
susceptibility regions was completed, with detection of several novel chromosomal regions,
and replication of several regions previously linked to associated phenotypes.
In order to determine the importance of these regions in asthma susceptibility and the impact
of environmental rink factors, the investigators l) evaluated the evidence for linkage in the
complete CSGA data using 2-point, multipoint and multilocus approaches for asthma and
associated phenotypes (including BHR, total serum IgE and skin test reactivity to
standardized allergens); 2) performed fine mapping studies of regions using additional
genetic markers to obtain a < 2 cM map; 3) identified candidate genes and novel sequence
variants; and 4) characterized a patient population with asthma to study identified variants
with respect to asthma severity and bronchial inflammation. These studies allowed
identification of asthma susceptibility genes and their variants, interactions with other
genes and environmental risk factors, as well as provided insight for the development of
improved treatment and ultimate prevention of asthma.
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