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Identification of PCDH1 as a Novel Susceptibility Gene for Bronchial Hyperresponsiveness

¹ Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, ³ Medical Biology, ⁴ Genetics, ⁵ Epidemiology, ⁶ Pathology, and ¹² Pulmonology, University Medical Center Groningen, University of Groningen, The Netherlands; ² Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina; ⁷ Respiratory Disease Area, Novartis Institutes for Biomedical Research, Horsham, United Kingdom; ⁸ Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland; ⁹ Infection, Inflammation, and Immunity Division, ¹⁰ Human Genetics Division, School of Medicine, University of Southampton, Southampton, United Kingdom; ¹¹ Arizona Respiratory Center, University of Arizona, Tucson, Arizona

Correspondence and requests for reprints should be addressed to Gerard H. Koppelman, M.D., Ph.D., Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, P.O. Box 30001, 9700 RB Groningen, The Netherlands. E-mail: g.h.koppelman{at}bkk.umcg.nl

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.

Key Words: bronchial hyperresponsiveness • asthma genetics • protocadherin-1 • cell adhesion • airway epithelium

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Asthma and bronchial hyperresponsiveness (BHR) are caused by multiple genetic and environmental factors. Linkage studies suggest the presence of one or more genes for asthma and bronchial hyperresponsiveness on chromosome 5q31-q33. What This Study Adds to the Field This study reports Protocadherin-1 as a novel gene for bronchial hyperresponsiveness on chromosome 5q31-q33. This gene encodes an adhesion molecule expressed in airway epithelium, which may implicate that a structural defect in the integrity of the airway epithelium contributes to the development of BHR.