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 - 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
SN - 1073-449X
VL - 201
SP - 540
EP - 554
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 5
ER -