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


OBJECTIVE
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.


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.
Koppelman
Gerard H
GH
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. g.h.koppelman@bkk.umcg.nl
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
D000328:Adult; D001249:Asthma / Q000235:genetics; D016535:Bronchial Hyperreactivity / Q000235:genetics*; D002648:Child; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D009426:Netherlands; D006113:United Kingdom; D014481:United States