Integration of Genomic and Genetic Approaches Implicates IREB2 as a COPD Susceptibility Gene

• Published in: American journal of human genetics Vol. 85; no. 4; pp. 493 - 502
• Main Authors: DeMeo, Dawn L., Mariani, Thomas, Bhattacharya, Soumyaroop, Srisuma, Sorachai, Lange, Christoph, Litonjua, Augusto, Bueno, Raphael, Pillai, Sreekumar G., Lomas, David A., Sparrow, David, Shapiro, Steven D., Criner, Gerard J., Kim, Hong P., Chen, Zhihua, Choi, Augustine M.K., Reilly, John, Silverman, Edwin K.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 09-10-2009; Cell Press; Elsevier
• Subjects: Aged; Biological and medical sciences; Case-Control Studies; Chronic obstructive pulmonary disease; Cohort Studies; Epithelial Cells - metabolism; Family Health; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Profiling; General aspects. Genetic counseling; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Genotype & phenotype; Humans; Iron Regulatory Protein 2 - genetics; Lung - metabolism; Male; Medical genetics; Medical sciences; Middle Aged; Models, Genetic; Molecular and cellular biology; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive - diagnosis; Pulmonary Disease, Chronic Obstructive - genetics; Ribonucleic acid; RNA; Smoking; Boston Massachusetts; Human; Lung disease; Chronic; Integration; Sensitivity; Respiratory disease; Bronchus disease; Genetics; Chronic obstructive pulmonary disease
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2009.09.004

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 × 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 × 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 ≤ 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 × 10
−7 to 6.4 × 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.