title: Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis Study. Alpha-1 Protocol.
abstract: Severe deficiency of alpha-1 antitrypsin has a highly variable clinical presentation. The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis α1 Study is a prospective, multicenter, cross-sectional study of adults older than age 35 years with PiZZ or PiMZ alpha-1 antitrypsin genotypes. It is designed to better understand if microbial factors influence this heterogeneity. Clinical symptoms, pulmonary function testing, computed chest tomography, exercise capacity, and bronchoalveolar lavage (BAL) will be used to define chronic obstructive pulmonary disease (COPD) phenotypes that can be studied with an integrated systems biology approach that includes plasma proteomics; mouth, BAL, and stool microbiome and virome analysis; and blood microRNA and blood mononuclear cell RNA and DNA profiling. We will rely on global genome, transcriptome, proteome, and metabolome datasets. Matched cohorts of PiZZ participants on or off alpha-1 antitrypsin augmentation therapy, PiMZ participants not on augmentation therapy, and control participants from the Subpopulations and Intermediate Outcome Measures in COPD Study who match on FEV1 and age will be compared. In the primary analysis, we will determine if the PiZZ individuals on augmentation therapy have a difference in lower respiratory tract microbes identified compared with matched PiZZ individuals who are not on augmentation therapy. By characterizing the microbiome in alpha-1 antitrypsin deficiency (AATD), we hope to define new phenotypes of COPD that explain some of the diversity of clinical presentations. As a unique genetic cause of COPD, AATD may inform typical COPD pathogenesis, and better understanding of it may illuminate the complex interplay between environment and genetics. Although the biologic approaches are hypothesis generating, the results may lead to development of novel biomarkers, better understanding of COPD phenotypes, and development of novel diagnostic and therapeutic trials in AATD and COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01832220).
authors.affiliation: 1 Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Charlie
authors.identifier: http://orcid.org/0000-0002-8109-8067
authors.initials: C
authors.lastname: Strange
authors.affiliation: 2 Barnes-Jewish Hospital/Washington University, St. Louis, Missouri.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Senior
authors.affiliation: 3 School of Medicine.
authors.forename: Frank
authors.initials: F
authors.lastname: Sciurba
authors.affiliation: 4 Graduate School of Public Health, and.
authors.forename: Scott
authors.initials: S
authors.lastname: O'Neal
authors.affiliation: 3 School of Medicine.
authors.forename: Alison
authors.initials: A
authors.lastname: Morris
authors.affiliation: 4 Graduate School of Public Health, and.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wisniewski
authors.affiliation: 5 National Jewish Health, Denver, Colorado.
authors.forename: Russell
authors.initials: R
authors.lastname: Bowler
authors.affiliation: 6 Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Harry S
authors.initials: HS
authors.lastname: Hochheiser
authors.affiliation: 6 Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Becich
authors.affiliation: 3 School of Medicine.|4 Graduate School of Public Health, and.
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 3 School of Medicine.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Leader
authors.affiliation: 7 J. Craig Venter Institute, Rockville, Maryland; and.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Methé
authors.affiliation: 8 Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.affiliation: 5 National Jewish Health, Denver, Colorado.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sandhaus
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018893:Bronchoalveolar Lavage; D003430:Cross-Sectional Studies; D017079:Exercise Tolerance; D005260:Female; D023281:Genomics; D005838:Genotype; D006801:Humans; D008297:Male; D064307:Microbiota; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis*; D011656:Pulmonary Emphysema / Q000175:diagnosis*; D012107:Research Design; D012129:Respiratory Function Tests; D012507:Sarcoidosis / Q000175:diagnosis*; D014057:Tomography, X-Ray Computed; D019896:alpha 1-Antitrypsin Deficiency / Q000175:diagnosis*
keywords: COPD; bronchoalveolar lavage; emphysema; lung; microbiome; phenotype