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Transforming Growth Factor-β Receptor-3 Is Associated with Pulmonary Emphysema

¹ Channing Laboratory and Center for Genomic Medicine, and ¹⁰ Division of Thoracic Radiology, Brigham and Women's Hospital, Boston, Massachusetts; ² Harvard Medical School, Boston, Massachusetts; ³ Division of Pulmonary and Critical Care Medicine, and ⁴ Division of Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, Maryland; ⁵ University of Cambridge, Cambridge, United Kingdom; ⁶ GlaxoSmithKline, Research Triangle Park, North Carolina; ⁷ Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada; ⁸ Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland; ⁹ Division of Biostatistics, School of Public Health, University of Minnesota, St. Paul, Minnesota; ¹¹ Veterans Affairs Boston Healthcare System and Boston University School of Medicine, Boston, Massachusetts; and ¹² Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Craig P. Hersh, M.D., M.P.H., Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115. E-mail: craig.hersh{at}channing.harvard.edu

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 FEV₁ (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.

Key Words: betaglycan • chronic obstructive pulmonary disease • computed tomography • linkage • single nucleotide polymorphism

CLINICAL RELEVANCE In this article we have identified transforming growth factor-β receptor 3 as a novel candidate gene for chronic obstructive pulmonary disease (COPD) susceptibility, in a relevant COPD pathway. We also demonstrate how more precise phenotypic characterization may aid in the identification of genes for a heterogeneous complex disease.

 

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