We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
The Effects of Rare Variants on Lung Function and Emphysema in SPIROMICS.
- Authors
Ortega, Victor E.; Xingnan Li; O'Neal, Wanda K.; Lackey, Lela; Ampleford, Elizabeth; Hawkins, Gregory A.; Grayeski, Philip J.; Laederach, Alain; Barjaktarevic, Igor; Barr, R. Graham; Cooper, Christopher; Couper, David; Han, MeiLan K.; Kanner, Richard E.; Kleerup, Eric C.; Martinez, Fernando J.; Paine III, Robert; Peters, Stephen P.; Pirozzi, Cheryl; Rennard, Stephen I.
- 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.
- Subjects
PULMONARY emphysema; GENOTYPES; PROTEASE inhibitors; PHENOTYPES; COMPUTED tomography; EXPIRATORY flow; RESEARCH; LUNGS; BLACK people; ELECTROPHORESIS; HISPANIC Americans; RESEARCH methodology; GENETIC polymorphisms; RESPIRATORY measurements; EVALUATION research; MEDICAL cooperation; GENETIC carriers; COMPARATIVE studies; OBSTRUCTIVE lung diseases; FORCED expiratory volume; RESEARCH funding; ALPHA 1-antitrypsin; SMOKING; WHITE people
- Publication
American Journal of Respiratory & Critical Care Medicine, 2020, Vol 201, Issue 5, p540
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.201904-0769OC