Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness

Gerard H. Koppelman; Deborah A. Meyers; Timothy D. Howard; S. Lilly Zheng; Greg A. Hawkins; Elizabeth J. Ampleford; Jianfeng Xu; Henk Koning; Marcel Bruinenberg; Ilja M. Nolte; Cleo C. Van Diemen; H. Marike Boezen; Wim Timens; Paul A. Whittaker; O. Colin Stine; Sheila J. Barton; John W. Holloway; Stephen T. Holgate; Penelope E. Graves; Fernando D. Martinez; Antoon J. Van Oosterhout; Eugene R. Bleecker; Dirkje S. Postma

doi:10.1164/rccm.200810-1621OC

Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness

Gerard H. Koppelman, Deborah A. Meyers, Timothy D. Howard, S. Lilly Zheng, Greg A. Hawkins, Elizabeth J. Ampleford, Jianfeng Xu, Henk Koning, Marcel Bruinenberg, Ilja M. Nolte, Cleo C. Van Diemen, H. Marike Boezen, Wim Timens, Paul A. Whittaker, O. Colin Stine, Sheila J. Barton, John W. Holloway, Stephen T. Holgate, Penelope E. Graves, Fernando D. MartinezAntoon J. Van Oosterhout, Eugene R. Bleecker, Dirkje S. Postma

Research output: Contribution to journal › Article › peer-review

95 Scopus citations

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 wasinvestigated using polymerase chain reaction, Western blotting, and immunohistochemistry. Measurements and Main Results: In seven out of eight populations (n 5 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:PCDH1is a novelgeneforBHRin adultsandchildren.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.

Original language	English (US)
Pages (from-to)	929-935
Number of pages	7
Journal	American Journal of Respiratory and Critical Care Medicine
Volume	180
Issue number	10
DOIs	https://doi.org/10.1164/rccm.200810-1621OC
State	Published - Nov 15 2009
Externally published	Yes

Keywords

Airway epithelium
Asthma genetics
Bronchial hyperresponsiveness
Cell adhesion
Protocadherin-1

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine
Critical Care and Intensive Care Medicine

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10.1164/rccm.200810-1621OC

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Koppelman, G. H., Meyers, D. A., Howard, T. D., Zheng, S. L., Hawkins, G. A., Ampleford, E. J., Xu, J., Koning, H., Bruinenberg, M., Nolte, I. M., Van Diemen, C. C., Boezen, H. M., Timens, W., Whittaker, P. A., Stine, O. C., Barton, S. J., Holloway, J. W., Holgate, S. T., Graves, P. E., ... Postma, D. 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. https://doi.org/10.1164/rccm.200810-1621OC

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, Van Oosterhout, AJ, Bleecker, ER & Postma, DS 2009, 'Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness', American Journal of Respiratory and Critical Care Medicine, vol. 180, no. 10, pp. 929-935. https://doi.org/10.1164/rccm.200810-1621OC

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title = "Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness",

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 wasinvestigated using polymerase chain reaction, Western blotting, and immunohistochemistry. Measurements and Main Results: In seven out of eight populations (n 5 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:PCDH1is a novelgeneforBHRin adultsandchildren.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.",

keywords = "Airway epithelium, Asthma genetics, Bronchial hyperresponsiveness, Cell adhesion, Protocadherin-1",

author = "Koppelman, {Gerard H.} and Meyers, {Deborah A.} and Howard, {Timothy D.} and Zheng, {S. Lilly} and Hawkins, {Greg A.} and Ampleford, {Elizabeth J.} and Jianfeng Xu and Henk Koning and Marcel Bruinenberg and Nolte, {Ilja M.} and {Van Diemen}, {Cleo C.} and Boezen, {H. Marike} and Wim Timens and Whittaker, {Paul A.} and Stine, {O. Colin} and Barton, {Sheila J.} and Holloway, {John W.} and Holgate, {Stephen T.} and Graves, {Penelope E.} and Martinez, {Fernando D.} and {Van Oosterhout}, {Antoon J.} and Bleecker, {Eugene R.} and Postma, {Dirkje S.}",

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doi = "10.1164/rccm.200810-1621OC",

language = "English (US)",

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pages = "929--935",

journal = "American Journal of Respiratory and Critical Care Medicine",

issn = "1073-449X",

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T1 - Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness

AU - Koppelman, Gerard H.

AU - Meyers, Deborah A.

AU - Howard, Timothy D.

AU - Zheng, S. Lilly

AU - Hawkins, Greg A.

AU - Ampleford, Elizabeth J.

AU - Xu, Jianfeng

AU - Koning, Henk

AU - Bruinenberg, Marcel

AU - Nolte, Ilja M.

AU - Van Diemen, Cleo C.

AU - Boezen, H. Marike

AU - Timens, Wim

AU - Whittaker, Paul A.

AU - Stine, O. Colin

AU - Barton, Sheila J.

AU - Holloway, John W.

AU - Holgate, Stephen T.

AU - Graves, Penelope E.

AU - Martinez, Fernando D.

AU - Van Oosterhout, Antoon J.

AU - Bleecker, Eugene R.

AU - Postma, Dirkje S.

PY - 2009/11/15

Y1 - 2009/11/15

N2 - 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 wasinvestigated using polymerase chain reaction, Western blotting, and immunohistochemistry. Measurements and Main Results: In seven out of eight populations (n 5 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:PCDH1is a novelgeneforBHRin adultsandchildren.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.

AB - 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 wasinvestigated using polymerase chain reaction, Western blotting, and immunohistochemistry. Measurements and Main Results: In seven out of eight populations (n 5 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:PCDH1is a novelgeneforBHRin adultsandchildren.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.

KW - Airway epithelium

KW - Asthma genetics

KW - Bronchial hyperresponsiveness

KW - Cell adhesion

KW - Protocadherin-1

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Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness

Abstract

Keywords

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