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Human Molecular Genetics Advance Access originally published online on June 2, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 15 1649-1656
DOI: 10.1093/hmg/ddh171
Human Molecular Genetics, Vol. 13, No. 15 © Oxford University Press 2004; all rights reserved

The transforming growth factor-ß1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD)

Juan C. Celedón1,2,3,*, Christoph Lange4, Benjamin A. Raby1,2,3, Augusto A. Litonjua1,2,3, Lyle J. Palmer1,3,5, Dawn L. DeMeo1,3,6, John J. Reilly3,6, David J. Kwiatkowski1,3, Harold A. Chapman7, Nan Laird4, Jody S. Sylvia1, Melvin Hernandez1, Frank E. Speizer1,3, Scott T. Weiss1,3 and Edwin K. Silverman1,3,6

1Channing Laboratory and 6Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, 2Division of Pulmonary and Critical Care Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, 3Harvard Medical School, Boston, MA, USA, 4Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA, 5Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Perth, Australia and 7Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California at San Francisco, San Francisco, CA, USA

Received April 6, 2004; Accepted May 19, 2004

Although cigarette smoking is the primary environmental risk factor, genetic risk factors likely influence the development of chronic obstructive pulmonary disease (COPD). Linkage analysis between short-tandem repeat markers on chromosome 19 and COPD phenotypes was followed by association analysis of single nucleotide polymorphisms in a gene on chromosome 19q [transforming growth factor-ß1 (TGFB1)] and COPD phenotypes in a family-based sample and a case–control study (cases with severe COPD and control subjects with significant history of smoking but no COPD). Stratification by smoking status substantially improved the evidence of linkage to chromosome 19q for COPD phenotypes. Among former and current smokers in the Boston Early-Onset COPD Study, there was significant evidence of linkage between chromosome 19q and pre-bronchodilator (pre-BD) FEV1 (LOD=3.30) and suggestive evidence of linkage between chromosome 19q and other COPD phenotypes. In these families, a SNP in the promoter region of TGFB1 (rs2241712) and two SNPs in the 3' genomic region of TGFB1 (rs2241718 and rs6957) were significantly associated with pre- and post-BD FEV1 (P<0.05). Among smokers in the COPD cases and control subjects, two SNPs in the promoter region of TGFB1 (rs2241712 and rs1800469) and one SNP in exon 1 of TGFB1 (rs1982073) were significantly associated with COPD (P≤0.02 in all cases). Chromosome 19q likely contains a genetic locus (or loci) that influences COPD through an interaction with cigarette smoking. We hypothesize that genetic variants in or near the TGFB1 gene influence the pathogenesis of COPD among cigarette smokers.

* To whom correspondence should be addressed at: Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115, USA. Tel: +1 6175250856; Fax: +1 6175250958; Email: juan.celedon{at}channing.harvard.edu


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