• Victor E Ortega, Xingnan Li, Wanda K O'Neal, Lela Lackey, Elizabeth Ampleford, Gregory A Hawkins, Philip J Grayeski, Alain Laederach, Igor Barjaktarevic, R Graham Barr, Christopher Cooper, David Couper, MeiLan K Han, Richard E Kanner, Eric C Kleerup, Fernando J Martinez, Robert Paine, Stephen P Peters, Cheryl Pirozzi, Stephen I Rennard, Prescott G Woodruff, Eric A Hoffman, Deborah A Meyers, Eugene R Bleecker, and NHLBI Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS).
• Center for Precision Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
• Am. J. Respir. Crit. Care Med. 2020 Mar 1; 201 (5): 540554540-554.

AbstractRationale: 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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