Variable Susceptibility to Cigarette Smoke-Induced Emphysema in 34 Inbred Strains of Mice Implicates Abi3bp in Emphysema Susceptibility

• Published in: American journal of respiratory cell and molecular biology Vol. 57; no. 3; pp. 367 - 375
• Main Authors: Radder, Josiah E, Gregory, Alyssa D, Leme, Adriana S, Cho, Michael H, Chu, Yanxia, Kelly, Neil J, Bakke, Per, Gulsvik, Amund, Litonjua, Augusto A, Sparrow, David, Beaty, Terri H, Crapo, James D, Silverman, Edwin K, Zhang, Yingze, Berndt, Annerose, Shapiro, Steven D
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01-09-2017
• Subjects: Alveoli; Animals; Asthma; Carrier Proteins - genetics; Carrier Proteins - metabolism; Chronic obstructive pulmonary disease; Cigarette smoke; Cigarettes; Computer Simulation; Disease; Disease Susceptibility; Emphysema; Experiments; Gene expression; Gene Expression Profiling; Genetic factors; Genome, Human; Genome-Wide Association Study; Genomes; Genomics; Humans; Inbreeding; Lung cancer; Lung diseases; Mice, Inbred Strains; Mutation - genetics; Obstructive lung disease; Original Research; Pulmonary Alveoli - metabolism; Pulmonary Alveoli - pathology; Pulmonary Emphysema - metabolism; Pulmonary Emphysema - pathology; Rodents; Senescence; Smoking - adverse effects; Studies; Thyroid gland; Abi3bp; animal model; COPD; emphysema
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2016-0220OC

Chronic obstructive pulmonary disease (COPD) is caused by a complex interaction of environmental exposures, most commonly cigarette smoke, and genetic factors. Chronic cigarette smoke exposure in the mouse is a commonly used animal model of COPD. We aimed to expand our knowledge about the variable susceptibility of inbred strains to this model and test for genetic variants associated with this trait. To that end, we sought to measure differential susceptibility to cigarette smoke-induced emphysema in the mouse, identify genetic loci associated with this quantitative trait, and find homologous human genes associated with COPD. Alveolar chord length (CL) in 34 inbred strains of mice was measured after 6 months of exposure to cigarette smoke. After testing for association, we connected a murine candidate locus to a published meta-analysis of moderate-to-severe COPD. We identified deleterious mutations in a candidate gene in silico and measured gene expression in extreme strains. A/J was the most susceptible strain in our survey (Δ CL 7.0 ± 2.2 μm) and CBA/J was the least susceptible (Δ CL -0.3 ± 1.2 μm). By integrating mouse and human genome-wide scans, we identified the candidate gene Abi3bp. CBA/J mice harbor predicted deleterious variants in Abi3bp, and expression of the gene differs significantly between CBA/J and A/J mice. This is the first report of susceptibility to cigarette smoke-induced emphysema in 34 inbred strains of mice, and Abi3bp is identified as a potential contributor to this phenotype.