The Effects of Rare Variants on Lung Function and Emphysema in SPIROMICS.

TitleThe Effects of Rare Variants on Lung Function and Emphysema in SPIROMICS.
Publication TypePublication
Year2020
AuthorsOrtega VE, Li X, O'Neal WK, Lackey L, Ampleford E, Hawkins GA, Grayeski PJ, Laederach A, Barjaktarevic I, R Barr G, Cooper C, Couper D, Han MK, Kanner RE, Kleerup EC, Martinez FJ, Paine R, Peters SP, Pirozzi C, Rennard SI, Woodruff PG, Hoffman EA, Meyers DA, Bleecker ER
Corporate AuthorsNHLBI Subpopulations and Intermediate Outcomes Measures in COPD Study(SPIROMICS)
JournalAm J Respir Crit Care Med
Volume201
Issue5
Pagination540-554
Date Published2020 03 01
ISSN1535-4970
KeywordsAdult, African Americans, Aged, Aged, 80 and over, alpha 1-Antitrypsin, Female, Forced Expiratory Volume, Genotype, Heterozygote, Hispanic or Latino, Humans, Isoelectric Focusing, Lung, Male, Maximal Midexpiratory Flow Rate, Middle Aged, phenotype, Polymorphism, Genetic, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema, smoking, Tomography, X-Ray Computed, Vital Capacity, Whites
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.

DOI10.1164/rccm.201904-0769OC
Alternate JournalAm J Respir Crit Care Med
PubMed ID31661293
PubMed Central IDPMC7047460
Grant ListU24 HL141762 / HL / NHLBI NIH HHS / United States
S10 OD018526 / OD / NIH HHS / United States
K08 HL118128 / HL / NHLBI NIH HHS / United States
R01 HL111527 / HL / NHLBI NIH HHS / United States
K24 HL137013 / HL / NHLBI NIH HHS / United States
U01 HL137880 / HL / NHLBI NIH HHS / United States
R01 HL142992 / HL / NHLBI NIH HHS / United States
P30 DK054759 / DK / NIDDK NIH HHS / United States
MS#: 
MS023
Manuscript Full Title: 
The Effects of Rare Variants on Lung Function and Emphysema in SPIROMICS.
Manuscript Lead/Corresponding Author Affiliation: 
Clinical Center: Winston-Salem (Wake Forest University Health Sciences)
ECI: 
Manuscript Status: 
Published and Public