Auyon J Ghosh1,2, Brian D Hobbs1,2,3, Matthew Moll1,2, Aabida Saferali1, Adel Boueiz1,2,3, Jeong H Yun1,2,3, Frank Sciurba4, Lucas Barwick5, Andrew H Limper6, Kevin Flaherty7, Gerard Criner8, Kevin K Brown9, Robert Wise10, Fernando J Martinez11, David Lomas12, Peter J Castaldi1,3, Vincent J Carey1,3, Dawn L DeMeo1,2,3, Michael H Cho1,2,3, Edwin K Silverman1,2,3, Craig P Hersh1,2,3. 1. Channing Division of Network Medicine and. 2. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. 3. Harvard Medical School, Harvard University, Boston, Massachusetts. 4. Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. 5. The Emmes Company, Rockville, Maryland. 6. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. 7. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan. 8. Department of Thoracic Medicine and Surgery, Temple University, Philadelphia, Pennsylvania. 9. Department of Medicine, National Jewish Health, Denver, Colorado. 10. Division of Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland. 11. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York; and. 12. University College London Respiratory Division of Medicine, University College London, London, United Kingdom.
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. Objectives: 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.
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. Objectives: 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.
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