Victor E Ortega1, Xingnan Li2, Wanda K O'Neal3, Lela Lackey4, Elizabeth Ampleford1, Gregory A Hawkins1, Philip J Grayeski3, Alain Laederach4, Igor Barjaktarevic5, R Graham Barr6, Christopher Cooper5, David Couper3, MeiLan K Han7, Richard E Kanner8, Eric C Kleerup5, Fernando J Martinez9, Robert Paine8, Stephen P Peters1, Cheryl Pirozzi8, Stephen I Rennard10,11, Prescott G Woodruff12, Eric A Hoffman13,14,15, Deborah A Meyers2, Eugene R Bleecker2. 1. Center for Precision Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina. 2. Department of Medicine, University of Arizona, Tucson, Arizona. 3. University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina. 4. Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 5. Department of Medicine, David Geffen School of Medicine, Los Angeles, California. 6. Columbia University Medical Center, New York City, New York. 7. Division of Pulmonary and Critical Care Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan. 8. Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah. 9. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medical College of Cornell University, New York City, New York. 10. Division of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Nebraska, Omaha, Nebraska. 11. Innovative Medicines and Early Development (IMED) Biotech Unit, AstraZeneca, Cambridge, United Kingdom. 12. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California; and. 13. Department of Radiology. 14. Department of Medicine, and. 15. Department of Biomedical Engineering, University of Iowa Carver College of Medicine, Iowa City, Iowa.
Abstract
Rationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A, member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial. Objectives: To comprehensively evaluate the effects of rare SERPINA1 variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations. Methods: DNA samples from 1,693 non-Hispanic white individuals, 385 African Americans, and 90 Hispanics with ≥20 pack-years smoking were resequenced for the identification of rare variants (allele frequency < 0.05) in 16.9 kB of SERPINA1.Measurements and Main Results: White PI Z heterozygotes confirmed by sequencing (MZ; n = 74) had lower post-bronchodilator FEV1 (P = 0.007), FEV1/FVC (P = 0.003), and greater computed tomography-based emphysema (P = 0.02) compared with 1,411 white individuals without PI Z, S, or additional rare variants denoted as VR. PI Z-containing compound heterozygotes (ZS/ZVR; n = 7) had lower FEV1/FVC (P = 0.02) and forced expiratory flow, midexpiratory phase (P = 0.009). Nineteen white heterozygotes for five non-S/Z coding variants associated with lower alpha-1 antitrypsin had greater computed tomography-based emphysema compared with those without rare variants. In African Americans, a 5' untranslated region insertion (rs568223361) was associated with lower alpha-1 antitrypsin and functional small airway disease (P = 0.007).Conclusions: In this integrative deep sequencing study of SERPINA1 with alpha-1 antitrypsin concentrations in a heavy smoker and chronic obstructive pulmonary disease cohort, we confirmed the effects of PI Z heterozygote and compound heterozygote genotypes. We demonstrate the cumulative effects of multiple SERPINA1 variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of SERPINA1 variation associated with respiratory disease in at-risk smokers.
Rationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A, member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial. Objectives: To comprehensively evaluate the effects of rare SERPINA1 variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations. Methods: DNA samples from 1,693 non-Hispanic white individuals, 385 African Americans, and 90 Hispanics with ≥20 pack-years smoking were resequenced for the identification of rare variants (allele frequency < 0.05) in 16.9 kB of SERPINA1.Measurements and Main Results: White PI Z heterozygotes confirmed by sequencing (MZ; n = 74) had lower post-bronchodilator FEV1 (P = 0.007), FEV1/FVC (P = 0.003), and greater computed tomography-based emphysema (P = 0.02) compared with 1,411 white individuals without PI Z, S, or additional rare variants denoted as VR. PI Z-containing compound heterozygotes (ZS/ZVR; n = 7) had lower FEV1/FVC (P = 0.02) and forced expiratory flow, midexpiratory phase (P = 0.009). Nineteen white heterozygotes for five non-S/Z coding variants associated with lower alpha-1 antitrypsin had greater computed tomography-based emphysema compared with those without rare variants. In African Americans, a 5' untranslated region insertion (rs568223361) was associated with lower alpha-1 antitrypsin and functional small airway disease (P = 0.007).Conclusions: In this integrative deep sequencing study of SERPINA1 with alpha-1 antitrypsin concentrations in a heavy smoker and chronic obstructive pulmonary disease cohort, we confirmed the effects of PI Z heterozygote and compound heterozygote genotypes. We demonstrate the cumulative effects of multiple SERPINA1 variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of SERPINA1 variation associated with respiratory disease in at-risk smokers.
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