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The Proceedings of the American Thoracic Society 3:440-443 (2006)
© 2006 The American Thoracic Society

The Genetics of Asthma

ADAM33 as an Example of a Susceptibility Gene

Stephen T. Holgate, Youwen Yang, Hans-Michael Haitchi, Rob M. Powell, John W. Holloway, Hajime Yoshisue, Yun Yun Pang, Julie Cakebread and Donna E. Davies

Division of Infection, Inflammation and Repair, School of Medicine, University of Southampton, and Southampton General Hospital, Southampton, United Kingdom

Correspondence and requests for reprints should be addressed to Professor S.T. Holgate, M.D., D.Sci., F.Med.Sci., Infection, Inflammation, and Repair Division, MP810, F Level, South Block, Southampton General Hospital, Southampton SO16 6YD, UK. E-mail: sth{at}soton.ac.uk

ABSTRACT

The ability to identify novel disease genes by positional cloning led to the identification of a disintegrin and metalloprotease (ADAM)33 gene on chromosome 20p13 as a susceptibility gene for asthma. Case-control and family-based association studies have mostly confirmed a link between ADAM33 and asthma. Its restricted expression to mesenchymal cells as well as its association with bronchial hyperresponsiveness and accelerated decline in lung function over time point strongly to its involvement in the structural airway components of asthma, such as remodeling. Extensive alternative splicing, expression during branching morphogensis in the developing fetus, impaired lung function in childhood, the production of a soluble form linked to chronic asthma, and tight epigenetic regulation indicate a level of complexity in the way ADAM33 influences disease phenotype. Its recent association with chronic obstructive pulmonary disease as well as with asthma and lung development points to functions relating to airway wall modeling and remodeling as a general morphogenetic repair gene rather than being restricted to asthma.

Key Words: ADAMs • asthma • biomarkers • hyperresponsiveness




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