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Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness

Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness
Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness
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.
bronchial hyperresponsiveness, asthma genetics, protocadherin-1, cell adhesion, airway epithelium
1073-449X
929-935
Koppelman, Gerard H.
8d04aab8-5795-4e62-b64a-de7e368c0d1d
Meyers, Deborah A.
14376cf3-c6e8-4c56-ba99-24c4e9849771
Howard, Timothy D.
c032f0ba-68f6-44df-a369-ca4fc21a1914
Zheng, S. Lilly
a257416e-6f30-40e8-bae9-1a145cad9435
Hawkins, Greg A.
43884ab1-952a-4fee-a6fd-85861190976d
Ampleford, Elizabeth J.
06bbd115-9946-48a0-86fe-af6668832301
Xu, Jianfeng
389d1b3f-cc76-48fa-81d1-94e14d818df0
Koning, Henk
f053a060-7e1c-4012-b21e-acd9883280ef
Bruinenberg, Marcel
7c4b3471-8898-4a2f-841b-128fe9b7c385
Nolte, Ilja M.
2d1a4ad0-9042-44f3-bd9d-768ee280f58d
van Diemen, Cleo C.
43c9958c-a3bc-4a64-b9da-ae948b372a23
Boezen, H. Marike
8f31af8f-7a5b-4840-82d5-a0d81ff8db6c
Timens, Wim
2610a41f-0c54-458b-a8c3-ae9cfb2c5e21
Whittaker, Paul A.
f66051b8-4cf8-4978-91d3-4e7cf555f4b4
Stine, O. Colin
7cacc403-b03a-4deb-a852-f5e5829ba443
Barton, Sheila J.
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Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Holgate, Stephen T.
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Graves, Penelope E.
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Martinez, Fernando D.
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van Oosterhout, Antoon J.
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Bleecker, Eugene R.
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Postma, Dirkje S.
23c1567d-a264-48a1-9ab4-01beda374e42
Koppelman, Gerard H.
8d04aab8-5795-4e62-b64a-de7e368c0d1d
Meyers, Deborah A.
14376cf3-c6e8-4c56-ba99-24c4e9849771
Howard, Timothy D.
c032f0ba-68f6-44df-a369-ca4fc21a1914
Zheng, S. Lilly
a257416e-6f30-40e8-bae9-1a145cad9435
Hawkins, Greg A.
43884ab1-952a-4fee-a6fd-85861190976d
Ampleford, Elizabeth J.
06bbd115-9946-48a0-86fe-af6668832301
Xu, Jianfeng
389d1b3f-cc76-48fa-81d1-94e14d818df0
Koning, Henk
f053a060-7e1c-4012-b21e-acd9883280ef
Bruinenberg, Marcel
7c4b3471-8898-4a2f-841b-128fe9b7c385
Nolte, Ilja M.
2d1a4ad0-9042-44f3-bd9d-768ee280f58d
van Diemen, Cleo C.
43c9958c-a3bc-4a64-b9da-ae948b372a23
Boezen, H. Marike
8f31af8f-7a5b-4840-82d5-a0d81ff8db6c
Timens, Wim
2610a41f-0c54-458b-a8c3-ae9cfb2c5e21
Whittaker, Paul A.
f66051b8-4cf8-4978-91d3-4e7cf555f4b4
Stine, O. Colin
7cacc403-b03a-4deb-a852-f5e5829ba443
Barton, Sheila J.
4f674382-ca0b-44ad-9670-e71a0b134ef0
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Holgate, Stephen T.
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Graves, Penelope E.
7c1f3f06-bdf9-4137-83c9-d52eeaea5455
Martinez, Fernando D.
c34c15ee-7b0f-486a-9acd-bc7b0020d4ea
van Oosterhout, Antoon J.
5a9ada43-46ba-4984-b9ef-a61d852062d8
Bleecker, Eugene R.
33edc1f3-57c5-44f6-93b7-311eea7e18ec
Postma, Dirkje S.
23c1567d-a264-48a1-9ab4-01beda374e42

Koppelman, Gerard H., Meyers, Deborah A., Howard, Timothy D., Zheng, S. Lilly, Hawkins, Greg A., Ampleford, Elizabeth J., Xu, Jianfeng, Koning, Henk, Bruinenberg, Marcel, Nolte, Ilja M., van Diemen, Cleo C., Boezen, H. Marike, Timens, Wim, Whittaker, Paul A., Stine, O. Colin, Barton, Sheila J., Holloway, John W., Holgate, Stephen T., Graves, Penelope E., Martinez, Fernando D., van Oosterhout, Antoon J., Bleecker, Eugene R. and Postma, Dirkje S. (2009) Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness. American Journal of Respiratory and Critical Care Medicine, 180 (10), 929-935. (doi:10.1164/rccm.200810-1621OC). (PMID:19729670)

Record type: Article

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.

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More information

Published date: 15 November 2009
Keywords: bronchial hyperresponsiveness, asthma genetics, protocadherin-1, cell adhesion, airway epithelium
Organisations: Human Genetics, Infection Inflammation & Immunity

Identifiers

Local EPrints ID: 69873
URI: http://eprints.soton.ac.uk/id/eprint/69873
ISSN: 1073-449X
PURE UUID: 2e7a3297-ef48-4743-b050-d5e1078ce948
ORCID for Sheila J. Barton: ORCID iD orcid.org/0000-0003-4963-4242
ORCID for John W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464

Catalogue record

Date deposited: 09 Dec 2009
Last modified: 14 Mar 2024 02:46

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Contributors

Author: Gerard H. Koppelman
Author: Deborah A. Meyers
Author: Timothy D. Howard
Author: S. Lilly Zheng
Author: Greg A. Hawkins
Author: Elizabeth J. Ampleford
Author: Jianfeng Xu
Author: Henk Koning
Author: Marcel Bruinenberg
Author: Ilja M. Nolte
Author: Cleo C. van Diemen
Author: H. Marike Boezen
Author: Wim Timens
Author: Paul A. Whittaker
Author: O. Colin Stine
Author: Penelope E. Graves
Author: Fernando D. Martinez
Author: Antoon J. van Oosterhout
Author: Eugene R. Bleecker
Author: Dirkje S. Postma

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