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Published ahead of print on April 7, 2005, doi:10.1165/rcmb.2005-0073OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 33, pp. 71-78, 2005
© 2005 American Thoracic Society
DOI: 10.1165/rcmb.2005-0073OC

Attempted Replication of Reported Chronic Obstructive Pulmonary Disease Candidate Gene Associations

Craig P. Hersh, Dawn L. DeMeo, Christoph Lange, Augusto A. Litonjua, John J. Reilly, David Kwiatkowski, Nan Laird, Jody S. Sylvia, David Sparrow, Frank E. Speizer, Scott T. Weiss and Edwin K. Silverman

Channing Laboratory, Pulmonary and Critical Care Division, and Hematology/Oncology Division, Department of Medicine, Brigham and Women's Hospital; Harvard Medical School; Department of Biostatistics, Harvard School of Public Health; and Veterans Affairs Medical Center, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Edwin K. Silverman, M.D., Ph.D., Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115. E-mail: ed.silverman{at}channing.harvard.edu

Case-control studies have successfully identified many significant genetic associations for complex diseases, but lack of replication has been a criticism of case-control genetic association studies in general. We selected 12 candidate genes with reported associations to chronic obstructive pulmonary disease (COPD) and genotyped 29 polymorphisms in a family-based study and in a case-control study. In the Boston Early-Onset COPD Study families, significant associations with quantitative and/or qualitative COPD-related phenotypes were found for the tumor necrosis factor (TNF)-{alpha} –308G>A promoter polymorphism (P < 0.02), a coding variant in surfactant protein B (SFTPB Thr131Ile) (P = 0.03), and the (GT)31 allele of the heme oxygenase (HMOX1) promoter short tandem repeat (P = 0.02). In the case-control study, the SFTPB Thr131Ile polymorphism was associated with COPD, but only in the presence of a gene-by-environment interaction term (P = 0.01 for both main effect and interaction). The 30-repeat, but not the 31-repeat, allele of HMOX1 was associated (P = 0.04). The TNF –308G>A polymorphism was not significant. In addition, the microsomal epoxide hydrolase "fast" allele (EPHX1 His139Arg) was significantly associated in the case-control study (P = 0.03). Although some evidence for replication was found for SFTPB and HMOX1, none of the previously published COPD genetic associations was convincingly replicated across both study designs.

Key Words: association studies • case-control studies • emphysema • genetics • single nucleotide polymorphism




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