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Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness.

ABSTRACT: 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.To identify a gene for BHR on chromosome 5q31-q33.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.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.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.

SUBMITTER: Koppelman GH

PROVIDER: S-EPMC2778155 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness.

Koppelman Gerard H GH Meyers Deborah A DA Howard Timothy D TD Zheng S Lilly SL Hawkins Greg A GA Ampleford Elizabeth J EJ Xu Jianfeng J Koning Henk H Bruinenberg Marcel M Nolte Ilja M IM van Diemen Cleo C CC Boezen H Marike HM Timens Wim W Whittaker Paul A PA Stine O Colin OC Barton Sheila J SJ Holloway John W JW Holgate Stephen T ST Graves Penelope E PE Martinez Fernando D FD van Oosterhout Antoon J AJ Bleecker Eugene R ER Postma Dirkje S DS

American journal of respiratory and critical care medicine 20090903 10

<h4>Rationale</h4>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.<h4>Objectives</h4>To identify a gene for BHR on chromosome 5q31-q33.<h4>Methods</h4>In 200 Dutch families ...[more]

PMID: 19729670

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Project description:BACKGROUND:Respiratory syncytial virus and other respiratory tract viruses lead to common colds in most infants, whereas a minority develop acute severe bronchiolitis often requiring hospitalization. We hypothesized that such an excessive response to respiratory tract viral infection is caused by host factors reflected in pre-existing increased bronchial responsiveness. OBJECTIVE:We sought to compare bronchial responsiveness and lung function in 1-month-old neonates who later develop acute severe bronchiolitis with those who do not. METHODS:We measured infant lung function (n=402) and bronchial responsiveness to methacholine (n=363) using the raised-volume rapid thoracoabdominal compression technique before any respiratory symptoms in 1-month-old neonates from the Copenhagen Prospective Study of Asthma in Childhood birth cohort born to mothers with asthma. The children were prospectively monitored for respiratory symptoms and given a diagnosis of acute severe bronchiolitis according to a fixed algorithm. RESULTS:Thirty-four (8.5%) infants had acute severe bronchiolitis before 2 years of age, 21 (62%) were hospitalized, and 23 (67%) of the cases were associated with respiratory syncytial virus. Children who later had acute severe bronchiolitis irrespective of viral species had a 2.5-fold increased responsiveness to methacholine (provocative dose of methacholine producing a 15% decrease in transcutaneous oxygen pressure [PD(15)]) at age 1 month compared with control subjects (median PD(15) in cases vs control subjects, 0.13 vs 0.33 ?mol; P=.01), whereas differences in baseline airflow were not significant for forced expiratory volume at 0.5 seconds (mean z score for cases vs control subjects, -0.18 vs -0.01; P=.36) and forced expiratory flow at 50% of forced vital capacity (mean z score for cases vs control subjects, -0.37 vs -0.09; P=.13). CONCLUSION:Bronchial hyperresponsiveness in at-risk neonates precedes acute severe bronchiolitis in response to infections with respiratory tract virus.

Dataset Information

Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness.

Publications

Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness.

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