Abstract:
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 was investigated using polymerase chain reaction, Western blotting, and immunohistochemistry. MEASUREMENTS AND MAIN RESULTS:In seven out of eight populations (n = 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:PCDH1 is a novel gene for BHR in adults and children. 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.
journal_name
Am J Respir Crit Care Medauthors
Koppelman GH,Meyers DA,Howard TD,Zheng SL,Hawkins GA,Ampleford EJ,Xu J,Koning H,Bruinenberg M,Nolte IM,van Diemen CC,Boezen HM,Timens W,Whittaker PA,Stine OC,Barton SJ,Holloway JW,Holgate ST,Graves PE,Martinez FD,doi
10.1164/rccm.200810-1621OCsubject
Has Abstractpub_date
2009-11-15 00:00:00pages
929-35issue
10eissn
1073-449Xissn
1535-4970pii
200810-1621OCjournal_volume
180pub_type
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