Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness

Gerard H. Koppelman, Deborah A. Meyers, Timothy D. Howard, S. Lilly Zheng, Greg A. Hawkins, Elizabeth J. Ampleford, Jianfeng Xu, Henk Koning, Marcel Bruinenberg, Ilja M. Nolte, Cleo C. Van Diemen, H. Marike Boezen, Wim Timens, Paul A. Whittaker, O. Colin Stine, Sheila J. Barton, John W. Holloway, Stephen T. Holgate, Penelope E. Graves, Fernando D. MartinezAntoon J. Van Oosterhout, Eugene R. Bleecker, Dirkje S. Postma

Research output: Contribution to journalArticlepeer-review

109 Scopus citations


Rationale: Asthma is a chronic inflammatory airway disease that affects more than 300 million individuals worldwide. Asthma is caused by interaction of genetic and environmental factors. Bronchial hyperresponsiveness (BHR) is a hallmark of asthma and results from increased sensitivity of the airways to physical or chemical stimulants. BHR and asthma are linked to chromosome 5q31-q33. Objectives: To identify a gene for BHR on chromosome 5q31-q33. Methods: In 200 Dutch families with asthma, linkage analysis and fine mapping were performed, and the Protocadherin 1 gene (PCDH1) was identified. PCDH1 was resequenced in 96 subjects from ethnically diverse populations to identify novel sequence variants. Subsequent replication studies were undertaken in seven populations from The Netherlands, the United Kingdom, and the United States, including two general population samples, two family samples, and three case-control samples. PCDH1 mRNA and protein expression wasinvestigated using polymerase chain reaction, Western blotting, and immunohistochemistry. Measurements and Main Results: In seven out of eight populations (n 5 6,168) from The Netherlands, United Kingdom, and United States, PCHD1 gene variants were significantly associated with BHR (P values, 0.005-0.05) This association was present in both families with asthma and general populations. PCDH1 mRNA and protein were expressed in airway epithelial cells and in macrophages. Conclusions:PCDH1is a novelgeneforBHRin adultsandchildren.The identification of PCDH1 as a BHR susceptibility gene may suggest that a structural defect in the integrity of the airway epithelium, the first line of defense against inhaled substances, contributes to the development of BHR.

Original languageEnglish (US)
Pages (from-to)929-935
Number of pages7
JournalAmerican journal of respiratory and critical care medicine
Issue number10
StatePublished - Nov 15 2009


  • Airway epithelium
  • Asthma genetics
  • Bronchial hyperresponsiveness
  • Cell adhesion
  • Protocadherin-1

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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