Journal article
The Effects of Rare SERPINA1 Variants on Lung Function and Emphysema in SPIROMICS
American journal of respiratory and critical care medicine, Vol.201(5), pp.540-554
03/01/2020
DOI: 10.1164/rccm.201904-0769OC
PMCID: PMC7047460
PMID: 31661293
Abstract
The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin,
(serpin peptidase inhibitor, clade A, member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial.
To comprehensively evaluate the effects of rare
variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations.
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
.
White PI Z heterozygotes confirmed by sequencing (MZ;
= 74) had lower post-bronchodilator FEV
(
= 0.007), FEV
/FVC (
= 0.003), and greater computed tomography-based emphysema (
= 0.02) compared with 1,411 white individuals without PI Z, S, or additional rare variants denoted as V
. PI Z-containing compound heterozygotes (ZS/ZV
;
= 7) had lower FEV
/FVC (
= 0.02) and forced expiratory flow, midexpiratory phase (
= 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 (
= 0.007).
In this integrative deep sequencing study of
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
variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of
variation associated with respiratory disease in at-risk smokers.
Details
- Title: Subtitle
- The Effects of Rare SERPINA1 Variants on Lung Function and Emphysema in SPIROMICS
- Creators
- Victor E Ortega - Wake Forest UniversityXingnan Li - University of ArizonaWanda K O'Neal - University of North Carolina at Chapel HillLela Lackey - University of North Carolina at Chapel HillElizabeth Ampleford - Wake Forest UniversityGregory A Hawkins - Wake Forest UniversityPhilip J Grayeski - University of North Carolina at Chapel HillAlain Laederach - University of North Carolina at Chapel HillIgor Barjaktarevic - University of California, Los AngelesR Graham Barr - Columbia UniversityChristopher Cooper - University of California, Los AngelesDavid Couper - University of North Carolina at Chapel HillMeiLan K Han - University of Michigan–Ann ArborRichard E Kanner - University of UtahEric C Kleerup - University of California at Los AngelesFernando J Martinez - Cornell UniversityRobert Paine III - University of UtahStephen P Peters - Wake Forest UniversityCheryl Pirozzi - University of UtahStephen I Rennard - AstraZenecaPrescott G Woodruff - University of California, San FranciscoEric A Hoffman - University of IowaDeborah A Meyers - University of ArizonaEugene R Bleecker - University of ArizonaNHLBI Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS)
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory and critical care medicine, Vol.201(5), pp.540-554
- DOI
- 10.1164/rccm.201904-0769OC
- PMID
- 31661293
- PMCID
- PMC7047460
- ISSN
- 1073-449X
- eISSN
- 1535-4970
- Grant note
- K08 HL118128 / NHLBI NIH HHS R01 HL111527 / NHLBI NIH HHS U24 HL141762 / NHLBI NIH HHS U01 HL137880 / NHLBI NIH HHS S10 OD018526 / NIH HHS R01 HL142992 / NHLBI NIH HHS P30 DK054759 / NIDDK NIH HHS K24 HL137013 / NHLBI NIH HHS
- Language
- English
- Date published
- 03/01/2020
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Internal Medicine
- Record Identifier
- 9984318789602771
Metrics
18 Record Views