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Integration of Genomic and Genetic Approaches Implicates IREB2 as a COPD Susceptibility Gene |
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| Authors: | Dawn L DeMeo Thomas Mariani Sorachai Srisuma Augusto Litonjua Raphael Bueno Sreekumar G Pillai David Sparrow Gerard J Criner Zhihua Chen Augustine MK Choi John Reilly |
| Institution: | 1 Channing Laboratory, Brigham and Women's Hospital, Boston, MA 02115, USA 2 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA 3 Division of Thoracic Surgery, Harvard University, Boston, MA 02115, USA 4 Harvard School of Public Health, Harvard University, Boston, MA 02115, USA 5 Harvard Medical School, Harvard University, Boston, MA 02115, USA 6 Division of Neonatology and Center for Pediatric Biomedical Research, University of Rochester, Rochester, NY 14642, USA 7 Department of Physiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 10700 Bangkok, Thailand 8 Genetics Division, Glaxo SmithKline Research and Development, Research Triangle Park, NC 27709, USA 9 Cambridge Institute for Medical Research, CB2 2XY Cambridge, UK 10 Boston Veteran Affairs Medical Center and the Pulmonary Center, Boston University Medical Center, Boston, MA 02130, USA 11 Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA 12 Temple Lung Center, Temple University School of Medicine, Philadelphia, PA 19140, USA |
| Abstract: | 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. |
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