Alpha-1 Antitrypsin MZ Heterozygosity Is an Endotype of Chronic Obstructive Pulmonary Disease
Auyon Ghosh, Brian D. Hobbs, Matthew Moll, Aabida Saferali, Adel Boueiz, Jeong H. Yun, Frank C. Sciurba, Lucas Barwick, Andrew H. Limper, Kevin R. Flaherty, Gerard J. Criner, Kevin K. Brown, Robert A. Wise, Fernando J. Martínez, David A. Lomas, Peter J. Castaldi, Vincent J. Carey, Dawn L. DeMeo, Michael H. Cho, Edwin K. Silverman, Craig P. Hersh, James D. Crapo, Edwin K. Silverman, Barry J. Make, Elizabeth A. Regan, Terri H. Beaty, Peter J. Castaldi, Michael H. Cho, Dawn L. DeMeo, Adel Boueiz, Marilyn G. Foreman, Auyon Ghosh, Lystra P. Hayden, Craig P. Hersh, Jacqueline B. Hetmanski, Brian D. Hobbs, John E. Hokanson, Wonji Kim, Nan M. Laird, Christoph Lange, Sharon M. Lutz, Merry‐Lynn McDonald, Dmitry Prokopenko, Matthew Moll, Jarrett D. Morrow, Dandi Qiao, Aabida Saferali, Phuwanat Sakornsakolpat, Emily S. Wan, Jeong H. Yun, Juan Pablo Centeno, Jean‐Paul Charbonnier, Harvey O. Coxson, Craig J. Galbán, MeiLan K. Han, Eric A. Hoffman, Stephen M. Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Estepar, Raul San Jose, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin J.R. van Beek, Bram van Ginneken, Eva M. van Rikxoort, Gonzalo Vegas‐Sánchez‐Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert L. Jensen, D. H. Everett, Jim Crooks, Katherine Pratte, Matthew Strand, Erin Austin, Gregory L. Kinney, Kendra A. Young, Surya P. Bhatt, Jessica Bon, Alejandro A. Díaz, Barry J. Make, Susan Murray, Elizabeth A. Regan, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush Banaei‐Kashani, Jeffrey L. Curtis, Perry G. Pernicano, Nicola A. Hanania
Abstract
RATIONALE: Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the AAT (alpha-1 antitrypsin) Z allele. However, it is not known if MZ subjects with COPD are phenotypically different from noncarriers (MM genotype) with COPD. OBJECTIVE: To assess if MZ subjects with COPD have different clinical features compared with MM subjects with COPD. METHODS: Genotypes of SERPINA1 were ascertained by using whole-genome sequencing data in three independent studies. We compared outcomes between MM subjects with COPD and MZ subjects with COPD in each study and combined the results in a meta-analysis. We performed longitudinal and survival analyses to compare outcomes in MM and MZ subjects with COPD over time. MEASUREMENTS AND MAIN RESULTS: We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had a lower FEV1% predicted and greater quantitative emphysema on chest computed tomography scans compared with MM subjects. In a meta-analysis, the FEV1 was 3.9% lower (95% confidence interval [CI], −6.55% to −1.26%) and emphysema (the percentage of lung attenuation areas <−950 HU) was 4.14% greater (95% CI, 1.44% to 6.84%) in MZ subjects. We found one gene, PGF (placental growth factor), to be differentially expressed in lung tissue from one study between MZ subjects and MM subjects. CONCLUSIONS: Carriers of the AAT Z allele (those who were MZ heterozygous) with COPD had lower lung function and more emphysema than MM subjects with COPD. Taken with the subtle differences in gene expression between the two groups, our findings suggest that MZ subjects represent an endotype of COPD.