Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations.
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.
Hersh
Craig P
CP
Channing Laboratory, Pulmonary and Critical Care Division, and Hematology/Oncology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Demeo
Dawn L
DL
Lange
Christoph
C
Litonjua
Augusto A
AA
Reilly
John J
JJ
Kwiatkowski
David
D
Laird
Nan
N
Sylvia
Jody S
JS
Sparrow
David
D
Speizer
Frank E
FE
Weiss
Scott T
ST
Silverman
Edwin K
EK
D000328:Adult; D000368:Aged; D000465:Algorithms; D000483:Alleles; D016022:Case-Control Studies; D004851:Epoxide Hydrolases / Q000235:genetics; D004852:Epoxy Compounds / Q000378:metabolism; D005192:Family Health; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D008957:Models, Genetic; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D037701:Pulmonary Surfactant-Associated Protein B / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid; D015203:Reproducibility of Results; D012907:Smoking; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D004852:Epoxy Compounds; D005819:Genetic Markers; D037701:Pulmonary Surfactant-Associated Protein B; D014409:Tumor Necrosis Factor-alpha; D006899:Mixed Function Oxygenases; D006419:Heme Oxygenase (Decyclizing); D004851:Epoxide Hydrolases