Asthma Clinical Trial
To identify the predisposing genes responsible for asthma and bronchial hyperresponsiveness (BHR) at region 5p13.3 in an inbred Hutterite community.
BACKGROUND:
Asthma is the most common chronic disease in industrialized nations, affecting more than10
million people in the U.S. alone. Familial aggregation and concordance rates in monozygotic
twins have suggested a genetic component to asthma. Dr. Ober and colleagues have been
conducting studies on the genetics of asthma and atopy in the Hutterites, an inbred
population of European origins that practices a communal lifestyle. A genome-wide screen
with 564 markers (average spacing 6 cM) was completed in an extended pedigree of 717
Hutterites who were well characterized with respect to asthma, atopy, and related
phenotypes. These individuals are descendants of only 64 ancestors who lived in the early
1700's to the early 1800's. Evidence for linkage with bronchial hyperresponsiveness (BHR) by
the likelihood ratio test extended over 30 centimorgans (cM) on chromosome 5p, with P-values
as small as 0.001. Additional evidence for linkage at this same location was evident by the
transmission disequilibrium test (P=0.0061). Typing additional markers in this region
identified a critical region of 2.4 cM, corresponding to 1.5 Mb of DNA, and a high risk
haplotype that is over transmitted to affected individuals.
The study was conducted in response to a Request for Applications, "Positional Candidate
Approaches in Asthma Gene Discovery" released in Ocatober, 1999.
DESIGN NARRATIVE:
Dr. Ober and colleagues characterized the 5p-linked BHR susceptibility locus in the inbred
Hutterites by positional cloning and replicating these findings in outbred, ethnically
diverse populations. They examined single nucleotide polymorphisms (SNPs) spaced about 10 kb
apart in each gene, and assessed the evidence for over transmission to affected offspring
with each SNP and SNP haplotypes. Associations in the Hutterites were replicated in two
outbred samples (a Caucasian sample from Germany, and an African American sample from
Chicago). The functional effects of associated variants were assessed by in vitro assays as
well as by genotype-phenotype studies in outbred samples that had been evaluated for asthma
and atopy phenotypes. Identifying asthma or BHR susceptibility loci may identify novel
pathways in asthma pathogenesis, thereby allowing for the development of new therapies and
intervention strategies for these common diseases.
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