Integration of genomic and genetic approaches implicates IREB2 as a COPD susceptibility gene.
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and is influenced by both genetic determinants and smoking. We identified genomic regions from 56 lung-tissue gene-expression microarrays and used them to select 889 SNPs to be tested for association with COPD. We genotyped SNPs in 389 severe COPD cases from the National Emphysema Treatment Trial and 424 cigarette-smoking controls from the Normative Aging Study. A total of 71 autosomal SNPs demonstrated at least nominal significance with COPD susceptibility (p = 3.4 x 10(-6) to 0.05). These 71 SNPs were evaluated in a family-based study of 127 probands with severe, early-onset COPD and 822 of their family members in the Boston Early-Onset COPD Study. We combined p values from the case-control and family-based analyses, setting p = 5.60 x 10(-5) as a conservative threshold for significance. Three SNPs in the iron regulatory protein 2 (IREB2) gene met this stringent threshold for significance, and four other IREB2 SNPs demonstrated combined p < 0.02. We demonstrated replication of association for these seven IREB2 SNPs (all p values < or = 0.02) in a family-based study of 3117 subjects from the International COPD Genetics Network; combined p values across all cohorts for the main phenotype of interest ranged from 1.6 x 10(-7) to 6.4 x 10(-4). IREB2 protein and mRNA were increased in lung-tissue samples from COPD subjects in comparison to controls. In summary, gene-expression and genetic-association results have implicated IREB2 as a COPD susceptibility gene.
DeMeo
Dawn L
DL
Channing Laboratory, Brigham and Women's Hospital, Boston, MA 02115, USA. dawn.demeo@channing.harvard.edu
Mariani
Thomas
T
Bhattacharya
Soumyaroop
S
Srisuma
Sorachai
S
Lange
Christoph
C
Litonjua
Augusto
A
Bueno
Raphael
R
Pillai
Sreekumar G
SG
Lomas
David A
DA
Sparrow
David
D
Shapiro
Steven D
SD
Criner
Gerard J
GJ
Kim
Hong P
HP
Chen
Zhihua
Z
Choi
Augustine M K
AM
Reilly
John
J
Silverman
Edwin K
EK
D000368:Aged; D016022:Case-Control Studies; D015331:Cohort Studies; D004847:Epithelial Cells / Q000378:metabolism; D005192:Family Health; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D023281:Genomics; D006801:Humans; D035942:Iron Regulatory Protein 2 / Q000235:genetics*; D008168:Lung / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000235:genetics*
D035942:Iron Regulatory Protein 2