TY - JOUR
T1 - The effects of rare SERPINA1 variants on lung function and emphysema in SPIROMICS
AU - Ortega, Victor E.
AU - Li, Xingnan
AU - O'Neal, Wanda K.
AU - Lackey, Lela
AU - Ampleford, Elizabeth
AU - Hawkins, Gregory A.
AU - Grayeski, Philip J.
AU - Laederach, Alain
AU - Barjaktarevic, Igor
AU - Barr, R. Graham
AU - Cooper, Christopher
AU - Couper, David
AU - Han, Mei Lan K.
AU - Kanner, Richard E.
AU - Kleerup, Eric C.
AU - Martinez, Fernando J.
AU - Paine, Robert
AU - Peters, Stephen P.
AU - Pirozzi, Cheryl
AU - Rennard, Stephen I.
AU - Woodruff, Prescott G.
AU - Hoffman, Eric A.
AU - Meyers, Deborah A.
AU - Bleecker, Eugene R.
N1 - Funding Information:
SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HHSN268200900020C) and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Co.; and Theravance Biopharma. Additional NIH grant funding included a career development award from the NHLBI (K08 HL118128, R01HL142992, and R01HL111527). The project officers from the Lung Division of the NHLBI were Lisa Postow and Lisa Viviano. Sequencing services were provided through the Resequencing and Genotyping Service by the Northwest Genomics Center at the University of Washington, Department of Genome Sciences, under U.S. federal government contract number HHSN268201100037C from the NHLBI.
Publisher Copyright:
© 2020 by the American Thoracic Society.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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 postbronchodilator 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 59 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.
AB - 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 postbronchodilator 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 59 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.
KW - Alpha-1 antitrypsin
KW - Chronic obstructive pulmonary disease
KW - Emphysema
KW - Rare variant
KW - SERPINA1
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U2 - 10.1164/rccm.201904-0769OC
DO - 10.1164/rccm.201904-0769OC
M3 - Article
C2 - 31661293
AN - SCOPUS:85080034967
VL - 201
SP - 540
EP - 554
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 5
ER -