Asthma Clinical Trial
To investigate the genetics of asthma by reexamining a carefully characterized population of patients with asthma, and by studying their families.
BACKGROUND:
The development of asthma requires exposure to inciting agents such as allergens and
environmental pollutants, as well as the presence of host or genetic factors. Understanding
the genetics of bronchial hyperresponsiveness (BHR) and allergy will delineate mechanisms
that are important in the pathogenesis and therapy of asthma. While both genetic and
environmental factors and their interactions are felt to be important, their precise role is
not fully understood.
DESIGN NARRATIVE:
The probands are from the 'asthma' center Beatrixoord in Haren, The Netherlands which was
started in 1962. In collaboration with Dr Dirkje Postma of Holland, data are available on
approximately 1200 patients who were first studied in 1963-1970 using the same protocol.
Family studies of the children and grandchildren of these original probands are underway. At
this time, 85 complete families have been characterized and clinical data and DNA are
available for analysis in Baltimore. Families are being ascertained so that the
investigators can test the fit of genetic models through segregation analyses. The major aim
of the study is to identify major genes for bronchial hyperresponsiveness (BHR) and asthma
by linkage with highly polymorphic DNA markers. Since allergy is commonly associated with
asthma, a second goal of the study is to identify major genes for atopy using similar
linkage studies. Allergic factors under study include skin test reactivity to common
allergens, serum total and specific IgE levels, and blood eosinophilia. Complex segregation
analysis will be performed separately for asthma, BHR and allergy. The most parsimonious
model from the segregation analysis will be used for linkage analysis. Initially, candidate
regions of the genome will be evaluated. Then, a systematic search of the genome will be
performed using highly polymorphic informative makers. When a linkage is detected, candidate
genes in that specific area will be studied.
The study was renewed in FY 1999 and in FY 2004 to: further characterize asthma and closely
related phenotypes; perform genetic modeling (complex segregation analysis) using one and
two locus models as well as bivariate segregation analysis; complete the genome wide screen;
fine map regions of interest and identify candidate genes, perform linkage disequilibrium
and haplotype sharing analyses; and perform case control analysis of susceptibility and
severity candidate genes for asthma.
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