Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness

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Abstract

Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component1,2. To date, linkage studies have identified more than a dozen genomic regions linked to asthma3. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log10 of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene4 as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04–0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors5. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.

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Figure 1: Linkage analysis and gene content of chromosome 20p13.
Figure 2: Linkage disequilibrium and case-control studies.
Figure 3: ADAM33 chromosomal region.
Figure 4: Expression analysis of the ADAM33 gene.

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Acknowledgements

We thank the patients and families that participated in this study, the nurses who assisted in the collection of clinical information and material, R. Saponjic, J. Wald, R. Dockhorn, S. Galant, W. Berger, and R. Townley for recruiting US families, and the Medical Research Council for additional UK family resources. We also thank N. Morton, L. Lowe and A. Bureau for statistical insight and support and A. Anisowicz, A. Baek, A. O'Connell, S. Raghuraman and K. Irenze for technical assistance. Sequencing support was provided by GenomeVision services of Genome Therapeutics Corporation. Some of the analyses used the program package SAGE, supported by the US Public Health Service.

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Correspondence to Tim P. Keith.

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