Transforming growth factor-β receptor-3 is associated with pulmonary emphysema

Craig P. Hersh, Nadia N. Hansel, Kathleen C. Barnes, David A. Lomas, Sreekumar G. Pillai, Harvey O. Coxson, Rasika A. Mathias, Nicholas M. Rafaels, Robert A. Wise, John E. Connett, Barbara J. Klanderman, Francine L. Jacobson, Ritu Gill, Augusto A. Litonjua, David Sparrow, John J. Reilly, Edwin K. Silverman, Alvar Agusti, Peter M.A. Calverley, Claudio F. DonnerRobert D. Levy, Barry J. Make, Peter D. Paré, Stephen I. Rennard, Jørgen Vestbo, Emiel F.M. Wouters

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome, including emphysema and airway disease. Phenotypes defined on the basis of chest computed tomography (CT) may decrease disease heterogeneity and aid in the identification of candidate genes for COPD subtypes. To identify these genes, we performed genome-wide linkage analysis in extended pedigrees from the Boston Early-Onset COPD Study, stratified by emphysema status (defined by chest CT scans) of the probands, followed by genetic association analysis of positional candidate genes. A region on chromosome 1p showed strong evidence of linkage to lung function traits in families of emphysema-predominant probands in the stratified analysis (LOD score = 2.99 in families of emphysema-predominant probands versus 1.98 in all families). Association analysis in 949 individuals from 127 early-onset COPD pedigrees revealed association for COPD-related traits with an intronic single-nucleotide polymorphism (SNP) in transforming growth factor-β receptor-3 (TGFBR3) (P = 0.005). This SNP was significantly associated with COPD affection status comparing 389 cases from the National Emphysema Treatment Trial to 472 control smokers (P = 0.04), and with FEV 1 (P = 0.004) and CT emphysema (P = 0.05) in 3,117 subjects from the International COPD Genetics Network. Gene-level replication of association with lung function was seen in 427 patients with COPD from the Lung Health Study. In conclusion, stratified linkage analysis followed by association testing identified TGFBR3 (betaglycan) as a potential susceptibility gene for COPD. Published human microarray and murine linkage studies have also demonstrated the importance of TGFBR3 in emphysema and lung function, and our group and others have previously found association of COPD-related traits with TGFB1, a ligand for TGFBR3.

Original languageEnglish (US)
Pages (from-to)324-331
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume41
Issue number3
DOIs
StatePublished - Sep 1 2009

Fingerprint

Pulmonary Emphysema
Pulmonary diseases
Growth Factor Receptors
Transforming Growth Factors
Chronic Obstructive Pulmonary Disease
Emphysema
Genes
Association reactions
Tomography
Lung
Genetic Association Studies
Pedigree
Polymorphism
Single Nucleotide Polymorphism
Thorax
Nucleotides
Microarrays
Chromosomes
betaglycan
Health

Keywords

  • Betaglycan
  • Chronic obstructive pulmonary disease
  • Computed tomography
  • Linkage
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Hersh, C. P., Hansel, N. N., Barnes, K. C., Lomas, D. A., Pillai, S. G., Coxson, H. O., ... Wouters, E. F. M. (2009). Transforming growth factor-β receptor-3 is associated with pulmonary emphysema. American journal of respiratory cell and molecular biology, 41(3), 324-331. https://doi.org/10.1165/rcmb.2008-0427OC

Transforming growth factor-β receptor-3 is associated with pulmonary emphysema. / Hersh, Craig P.; Hansel, Nadia N.; Barnes, Kathleen C.; Lomas, David A.; Pillai, Sreekumar G.; Coxson, Harvey O.; Mathias, Rasika A.; Rafaels, Nicholas M.; Wise, Robert A.; Connett, John E.; Klanderman, Barbara J.; Jacobson, Francine L.; Gill, Ritu; Litonjua, Augusto A.; Sparrow, David; Reilly, John J.; Silverman, Edwin K.; Agusti, Alvar; Calverley, Peter M.A.; Donner, Claudio F.; Levy, Robert D.; Make, Barry J.; Paré, Peter D.; Rennard, Stephen I.; Vestbo, Jørgen; Wouters, Emiel F.M.

In: American journal of respiratory cell and molecular biology, Vol. 41, No. 3, 01.09.2009, p. 324-331.

Research output: Contribution to journalArticle

Hersh, CP, Hansel, NN, Barnes, KC, Lomas, DA, Pillai, SG, Coxson, HO, Mathias, RA, Rafaels, NM, Wise, RA, Connett, JE, Klanderman, BJ, Jacobson, FL, Gill, R, Litonjua, AA, Sparrow, D, Reilly, JJ, Silverman, EK, Agusti, A, Calverley, PMA, Donner, CF, Levy, RD, Make, BJ, Paré, PD, Rennard, SI, Vestbo, J & Wouters, EFM 2009, 'Transforming growth factor-β receptor-3 is associated with pulmonary emphysema', American journal of respiratory cell and molecular biology, vol. 41, no. 3, pp. 324-331. https://doi.org/10.1165/rcmb.2008-0427OC
Hersh, Craig P. ; Hansel, Nadia N. ; Barnes, Kathleen C. ; Lomas, David A. ; Pillai, Sreekumar G. ; Coxson, Harvey O. ; Mathias, Rasika A. ; Rafaels, Nicholas M. ; Wise, Robert A. ; Connett, John E. ; Klanderman, Barbara J. ; Jacobson, Francine L. ; Gill, Ritu ; Litonjua, Augusto A. ; Sparrow, David ; Reilly, John J. ; Silverman, Edwin K. ; Agusti, Alvar ; Calverley, Peter M.A. ; Donner, Claudio F. ; Levy, Robert D. ; Make, Barry J. ; Paré, Peter D. ; Rennard, Stephen I. ; Vestbo, Jørgen ; Wouters, Emiel F.M. / Transforming growth factor-β receptor-3 is associated with pulmonary emphysema. In: American journal of respiratory cell and molecular biology. 2009 ; Vol. 41, No. 3. pp. 324-331.
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AU - Sparrow, David

AU - Reilly, John J.

AU - Silverman, Edwin K.

AU - Agusti, Alvar

AU - Calverley, Peter M.A.

AU - Donner, Claudio F.

AU - Levy, Robert D.

AU - Make, Barry J.

AU - Paré, Peter D.

AU - Rennard, Stephen I.

AU - Vestbo, Jørgen

AU - Wouters, Emiel F.M.

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