Transforming growth factor-beta receptor-3 is associated with pulmonary emphysema.
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-beta 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.
Hersh
Craig P
CP
Channing Laboratory and Center for Genomic Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. craig.hersh@channing.harvard.edu
Hansel
Nadia N
NN
Barnes
Kathleen C
KC
Lomas
David A
DA
Pillai
Sreekumar G
SG
Coxson
Harvey O
HO
Mathias
Rasika A
RA
Rafaels
Nicholas M
NM
Wise
Robert A
RA
Connett
John E
JE
Klanderman
Barbara J
BJ
Jacobson
Francine L
FL
Gill
Ritu
R
Litonjua
Augusto A
AA
Sparrow
David
D
Reilly
John J
JJ
Silverman
Edwin K
EK
D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002986:Clinical Trials as Topic; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008126:Lod Score; D008297:Male; D051379:Mice; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011509:Proteoglycans / Q000235:genetics* / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000235:genetics / Q000503:physiopathology; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D013147:Spirometry; D011795:Surveys and Questionnaires; D014057:Tomography, X-Ray Computed
D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C071736:betaglycan