@article{b2fad64ec9d04fd795717234d0269bc7,
title = "Alpha-1 Antitrypsin MZ Heterozygosity Is an Endotype of Chronic Obstructive Pulmonary Disease",
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], 26.55% to 21.26%) and emphysema (the percentage of lung attenuation areas,2950 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.",
keywords = "Alpha-1 antitrypsin, Chronic obstructive pulmonary disease, Meta-analysis, RNA sequencing",
author = "Ghosh, {Auyon J.} and Hobbs, {Brian D.} and Matthew Moll and Aabida Saferali and Adel Boueiz and Yun, {Jeong H.} and Frank Sciurba and Lucas Barwick and Limper, {Andrew H.} and Kevin Flaherty and Gerard Criner and Brown, {Kevin K.} and Robert Wise and Martinez, {Fernando J.} and David Lomas and Castaldi, {Peter J.} and Carey, {Vincent J.} and DeMeo, {Dawn L.} and Cho, {Michael H.} and Silverman, {Edwin K.} and Hersh, {Craig P.}",
note = "Funding Information: Supported by NIH grants R01HL130512, R01HL125583, U01HL089856, U01HL089897, R01HL124233, R01HL147326, and T32HL007427 and a grant from the Alpha-1 Foundation. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program were supported by the NHLBI. Genome sequencing for “NHLBI TOPMed: COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD])” study (phs000951) was performed at the Broad Genomics Institute Platform (HHSN268201500014C) and the Northwest Genomics Center (3R01HL089856-08S1). Genome Sequencing for “NHLBI TOPMed: ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints)” study (phs001472) was performed at the McDonnell Genome Institute (HHSN268201600037I). Genome Sequencing for “NHLBI TOPMed: LTRC (Lung Tissue Research Consortium)” study (phs001662) was performed at the Broad Genomic Institute Platform (HHSN268201600034I). RNA sequencing for “NHLBI TOPMed: LTRC” study (phs001662) was performed at the Northwest Genomics Center (HHSN268201600032I). Core support, including centralized genomic read mapping and genotype calling, together with variant quality metrics and filtering, was provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support, including phenotype harmonization, data management, sample-identity quality control, and general program coordination, was provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). The COPDGene phase 3 project described was supported by award U01 HL089897 and award U01 HL089856 from the NHLBI. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI or the NIH. The COPDGene study is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. Publisher Copyright: {\textcopyright} 2022 by the American Thoracic Society",
year = "2022",
month = feb,
day = "1",
doi = "10.1164/rccm.202106-1404OC",
language = "English (US)",
volume = "205",
pages = "313--323",
journal = "American Review of Respiratory Disease",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "3",
}