α1-Antitrypsin Gene Variation Associates With Asthma Exacerbations and Related Health Care Utilization

doi:10.1016/j.jaip.2025.01.039

α₁-Antitrypsin Gene Variation Associates With Asthma Exacerbations and Related Health Care Utilization

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Background: α₁-Antitrypsin deficiency is caused by rare pathogenic variants in SERPINA1, the strongest genetic risk factor for chronic obstructive pulmonary disease. Few studies have evaluated the effects of SERPINA1 variation on asthma severity accounting for critical gene-by-environment interactions with smoking. Objective: To characterize the influence of SERPINA1 variation on asthma severity. Methods: DNA samples from 847 non-Hispanic White and 446 African American participants from the Severe Asthma Research Program underwent SERPINA1 resequencing to identify rare variants. An independent population of 1955 individuals with asthma and α₁-antitrypsin concentrations from a Cleveland Clinic Health System (CCHS) database were evaluated for severity measures. Results: In White participants, a history of minimum smoking significantly interacted with SERPINA1 low-to-rare frequency variation to determine risk for asthma-related health care utilization. This was attributed to protease inhibitor type Z heterozygotes (MZ, N = 11), who had a higher frequency of emergency department (ED) visits (6 [54.5%] MZ heterozygotes, odds ratio [OR] = 7.60, 95% confidence interval [CI] = 1.71-39.7, P = .010), hospitalization (5 [45.5%], OR = 16.1, 95% CI = 2.64-150.4, P = .0050) in the past year, and lifetime intensive care unit (ICU) admissions (6 [54.5%], OR = 12.5, 95% CI = 2.44-75.6, P = .0032) compared with 146 individuals without SERPINA1 variants (30 [20.5%] reporting ED visits, 17 [11.6%] hospitalization, and 15 [10.3%] ICU admission). SERPINA1 variant-by–ever smoking interactions in African American participants for ED visits (P = .069) were related to 4 of 6 compound heterozygotes reporting an ED visit. In CCHS, α₁-antitrypsin concentrations were inversely associated with moderate-to-severe asthma risk (OR = 0.97 per 10 mg/dL increase in α₁-antitrypsin, 95% CI = 0.94-0.99, P = .010) and exacerbations (OR = 0.84 per 10 mg/dL, 95% CI = 0.76-0.94, P = .002). Conclusions: SERPINA1 variation and α₁-antitrypsin concentrations impact asthma severity through gene-environment interactions with minimum smoking.

Original language	English
Pages (from-to)	1634-1646.e7
Journal	Journal of Allergy and Clinical Immunology: In Practice
Volume	13
Issue number	7
DOIs	https://doi.org/10.1016/j.jaip.2025.01.039
State	Published - Jul 2025

Bibliographical note

Publisher Copyright:
© 2025 American Academy of Allergy, Asthma & Immunology

Funding

Conflicts of interest: The authors, many of whom receive funding from the National Institutes of Health (NIH) or the Foundation of the NIH, report no financial or personal relationships that could inappropriately influence (bias) this work, with the following exceptions: V. E. Ortega reported receiving funding from the NIH National Heart, Lung, and Blood Institute (NHLBI) in the form of a K08 training award (Mentored Clinical Scientist Research Career Development Award, NIH HL118128, and R01HL142992. Principle Investigator: V. E. Ortega). He also reported consultancy fees from CSL Behring. V. Tejwani reports receiving funding from the NIH/NHLBI. M. Castro reports receiving University Grant Funding from the NIH, American Lung Association, and PCORI, and Pharmaceutical Grant Funding from AstraZeneca, Chiesi, Novartis, GSK, and Sanofi-Aventis; consultancy fees from Genentech, Theravance, VIDA, Teva, and Sanofi-Aventis; speaker fees from AstraZeneca, Genentech, GSK, Regeneron, Sanofi, and Teva; and royalties from Elsevier. L. Denlinger reports receiving grants from the NIH/NHLBI, consultancy fees from AstraZeneca and Sanofi-Regeneron during the conduct of the study, and funding to support the extension of the longitudinal phase of the SARP cohort from AstraZeneca, Boehringer-Ingelheim, Genentech, GSK, Sanofi-Genzyme-Regeneron, and Teva. S. C. Erzurum reports receiving grants from the NIH during the conduct of the study and serves as Chair of the ABIM Pulmonary Disease Board. J. V. Fahy reports receiving grants from the NIH/NHLBI, grants from Boehringer-Ingelheim during the conduct of the study, and personal fees from Boehringer-Ingelheim, Pieris, Arrowhead Pharmaceuticals, and Gossamer outside the submitted work. He also has a patent US20110123530A1 “Compositions and methods for treating and diagnosing asthma” issued, a patent WO2014153009A2 “Thiosaccharide mucolytic agents” issued, and a patent WO2017197360 “CT Mucus Score”—A new scoring system that quantifies airway mucus impaction using computed tomography lung scans. E. Israel reports receiving personal fees from AstraZeneca, Biometry, Entrinsic Health Solutions, Equillium, Genentech, GlaxoSmithKline, Merck, Novartis, 4D Pharma, Pneuma Respiratory, Regeneron Pharmaceuticals, Sanofi Genzyme, Sienna Biopharmaceutical, TEVA Specialty Pharmaceuticals, and Vitaeris, Inc; grants from AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Merck, Novartis, Sanofi, TEVA, and Vifor-Pharma; nonfinancial support from Circassia, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Merck, Teva Specialty Pharmaceuticals, and Vifor-Pharma; and other from Vorso Corp. N. N. Jarjour reports receiving grants from the NIH/NHLBI, consultancy fees from AstraZeneca and Boehringer-Ingelheim, and funding support for the extension of the longitudinal phase of the SARP cohort from AstraZeneca, Boehringer-Ingelheim, Genentech, GSK, Sanofi-Genzyme-Regeneron, and Teva. B. Levy reports receiving grants from the NIH during the conduct of the study; other from Nocion Therapeutics and Entrinsic Health; grants and personal fees from Sanofi; personal fees from Pieris Pharmaceuticals, Novartis, AstraZeneca, Corbus Pharmaceuticals, Gossamer Bio, Metera Pharmaceuticals, and Teva; and grants from Samsung Research America. D. Mauger reports receiving grant support from the NIH, AstraZeneca, Boehringer-Ingelheim, Genentech, GSK, Sanofi-Genzyme-Regeneron, and Teva. W. C. Moore reports receiving grants from the NIH; grants from AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi-Genzyme-Regeneron, and Teva during the conduct of the study; grants and personal fees from AstraZeneca and Sanofi-Regeneron; and grants from Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Gossamer, and Cumberland Pharmaceuticals. S. E. Wenzel reports receiving grants from the NIH and personal fees from AstraZeneca; grants and personal fees from GSK during the conduct of the study; grants and personal fees from Sanofi-Regeneron; grants from Boehringer-Ingelheim, Novartis, and Teva; and personal fees from Pieris. P. Woodruff reports receiving consultancy fees from AstraZeneca, Theravance, Glenmark Pharmaceuticals, Sanofi, and Regeneron, and funding from Genetech and the COPD Foundation. E. R. Bleecker reports receiving grants from the NIH; funding for clinical trials through his employer, Wake Forest School of Medicine and University of Arizona for AstraZeneca, MedImmune, Boehringer Ingelheim, Genentech, Johnson and Johnson (Janssen), Novartis, Regeneron, and Sanofi Genzyme; and personal fees as a consultant from AstraZeneca, MedImmune, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Regeneron, and Sanofi Genzyme. The rest of the authors declare that they have no relevant conflicts of interest. This work was funded by the National Institutes of Health grants R01 HL142992, K08 HL118128, R01 HL111527, HL69116, HL69167, HL69170, HL69174, U10 HL109164, U10 HL109257, U10 HL109146, U10 HL109172, U10 HL109250, U10 HL109168, U10 HL109152, and U10 HL109086. 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 US Federal Government contract number HHSN268201100037C, the Trans-Omics for Precision Medicine program, and the National Heart, Lung, and Blood Institute (NHLBI)-sponsored GO Exome Sequencing Program, all of which were sponsored by the NHLBI.

Funders	Funder number
AstraZeneca
Chiesi Farmaceutici S.p.A.
Novartis
Genetech
Sanofi
Celltron/Teva
American Lung Association
Sienna Biopharmaceutical
Vorso Corp
Merck
Sanofi Genzyme
PCORI
MedImmune
Cumberland Pharmaceuticals Inc.
Vifor Pharma Management
Regeneron Pharmaceuticals
Sanofi-Genzyme-Regeneron
Boehringer-Ingelheim
Genentech Incorporated
COPD Foundation
Johnson and Johnson Pharmaceutical Research and Development
GlaxoSmithKline
Samsung Research America
Teva Specialty Pharmaceuticals
The George Washington University
Wake Forest School of Medicine and University of Arizona for AstraZeneca
GSK
Nocion Therapeutics and Entrinsic Health
Glenmark Pharmaceuticals Ltd
NIH National Heart, Lung, and Blood Institute
ABIM Pulmonary Disease Board
National Institutes of Health (NIH)	R01 HL111527, HL69174, HL69170, HL69116, HL69167, U10 HL109257, U10 HL109146, U10 HL109168, U10 HL109164, U10 HL109152, U10 HL109086, U10 HL109250, U10 HL109172
National Heart, Lung, and Blood Institute (NHLBI)	K08 HL118128, R01HL142992
Department of Genome Sciences	HHSN268201100037C

Keywords

Alpha1-antitrypsin
Asthma
Exacerbations
Genetics
Lung function
Rare variant
SERPINA1

ASJC Scopus subject areas

Immunology and Allergy

Access to Document

10.1016/j.jaip.2025.01.039

Cite this

@article{29cadea468ed4c9fabc099b06cd30d17,

title = "α1-Antitrypsin Gene Variation Associates With Asthma Exacerbations and Related Health Care Utilization",

abstract = "Background: α1-Antitrypsin deficiency is caused by rare pathogenic variants in SERPINA1, the strongest genetic risk factor for chronic obstructive pulmonary disease. Few studies have evaluated the effects of SERPINA1 variation on asthma severity accounting for critical gene-by-environment interactions with smoking. Objective: To characterize the influence of SERPINA1 variation on asthma severity. Methods: DNA samples from 847 non-Hispanic White and 446 African American participants from the Severe Asthma Research Program underwent SERPINA1 resequencing to identify rare variants. An independent population of 1955 individuals with asthma and α1-antitrypsin concentrations from a Cleveland Clinic Health System (CCHS) database were evaluated for severity measures. Results: In White participants, a history of minimum smoking significantly interacted with SERPINA1 low-to-rare frequency variation to determine risk for asthma-related health care utilization. This was attributed to protease inhibitor type Z heterozygotes (MZ, N = 11), who had a higher frequency of emergency department (ED) visits (6 [54.5\%] MZ heterozygotes, odds ratio [OR] = 7.60, 95\% confidence interval [CI] = 1.71-39.7, P = .010), hospitalization (5 [45.5\%], OR = 16.1, 95\% CI = 2.64-150.4, P = .0050) in the past year, and lifetime intensive care unit (ICU) admissions (6 [54.5\%], OR = 12.5, 95\% CI = 2.44-75.6, P = .0032) compared with 146 individuals without SERPINA1 variants (30 [20.5\%] reporting ED visits, 17 [11.6\%] hospitalization, and 15 [10.3\%] ICU admission). SERPINA1 variant-by–ever smoking interactions in African American participants for ED visits (P = .069) were related to 4 of 6 compound heterozygotes reporting an ED visit. In CCHS, α1-antitrypsin concentrations were inversely associated with moderate-to-severe asthma risk (OR = 0.97 per 10 mg/dL increase in α1-antitrypsin, 95\% CI = 0.94-0.99, P = .010) and exacerbations (OR = 0.84 per 10 mg/dL, 95\% CI = 0.76-0.94, P = .002). Conclusions: SERPINA1 variation and α1-antitrypsin concentrations impact asthma severity through gene-environment interactions with minimum smoking.",

keywords = "Alpha1-antitrypsin, Asthma, Exacerbations, Genetics, Lung function, Rare variant, SERPINA1",

author = "Ortega, \{Victor E.\} and Vickram Tejwani and Shrivastav, \{Abhishek Kumar\} and Sara Pasha and Zein, \{Joe G.\} and Meher Boorgula and Mario Castro and Loren Denlinger and Erzurum, \{Serpil C.\} and Fahy, \{John V.\} and Elliot Israel and Jarjour, \{Nizar N.\} and Bruce Levy and David Mauger and Moore, \{Wendy C.\} and Wenzel, \{Sally E.\} and Prescott Woodruff and Hawkins, \{Gregory A.\} and Bleecker, \{Eugene R.\} and Meyers, \{Deborah A.\}",

note = "Publisher Copyright: {\textcopyright} 2025 American Academy of Allergy, Asthma \& Immunology",

year = "2025",

month = jul,

doi = "10.1016/j.jaip.2025.01.039",

language = "English",

volume = "13",

pages = "1634--1646.e7",

number = "7",

}

TY - JOUR

T1 - α1-Antitrypsin Gene Variation Associates With Asthma Exacerbations and Related Health Care Utilization

AU - Ortega, Victor E.

AU - Tejwani, Vickram

AU - Shrivastav, Abhishek Kumar

AU - Pasha, Sara

AU - Zein, Joe G.

AU - Boorgula, Meher

AU - Castro, Mario

AU - Denlinger, Loren

AU - Erzurum, Serpil C.

AU - Fahy, John V.

AU - Israel, Elliot

AU - Jarjour, Nizar N.

AU - Levy, Bruce

AU - Mauger, David

AU - Moore, Wendy C.

AU - Wenzel, Sally E.

AU - Woodruff, Prescott

AU - Hawkins, Gregory A.

AU - Bleecker, Eugene R.

AU - Meyers, Deborah A.

PY - 2025/7

Y1 - 2025/7

N2 - Background: α1-Antitrypsin deficiency is caused by rare pathogenic variants in SERPINA1, the strongest genetic risk factor for chronic obstructive pulmonary disease. Few studies have evaluated the effects of SERPINA1 variation on asthma severity accounting for critical gene-by-environment interactions with smoking. Objective: To characterize the influence of SERPINA1 variation on asthma severity. Methods: DNA samples from 847 non-Hispanic White and 446 African American participants from the Severe Asthma Research Program underwent SERPINA1 resequencing to identify rare variants. An independent population of 1955 individuals with asthma and α1-antitrypsin concentrations from a Cleveland Clinic Health System (CCHS) database were evaluated for severity measures. Results: In White participants, a history of minimum smoking significantly interacted with SERPINA1 low-to-rare frequency variation to determine risk for asthma-related health care utilization. This was attributed to protease inhibitor type Z heterozygotes (MZ, N = 11), who had a higher frequency of emergency department (ED) visits (6 [54.5%] MZ heterozygotes, odds ratio [OR] = 7.60, 95% confidence interval [CI] = 1.71-39.7, P = .010), hospitalization (5 [45.5%], OR = 16.1, 95% CI = 2.64-150.4, P = .0050) in the past year, and lifetime intensive care unit (ICU) admissions (6 [54.5%], OR = 12.5, 95% CI = 2.44-75.6, P = .0032) compared with 146 individuals without SERPINA1 variants (30 [20.5%] reporting ED visits, 17 [11.6%] hospitalization, and 15 [10.3%] ICU admission). SERPINA1 variant-by–ever smoking interactions in African American participants for ED visits (P = .069) were related to 4 of 6 compound heterozygotes reporting an ED visit. In CCHS, α1-antitrypsin concentrations were inversely associated with moderate-to-severe asthma risk (OR = 0.97 per 10 mg/dL increase in α1-antitrypsin, 95% CI = 0.94-0.99, P = .010) and exacerbations (OR = 0.84 per 10 mg/dL, 95% CI = 0.76-0.94, P = .002). Conclusions: SERPINA1 variation and α1-antitrypsin concentrations impact asthma severity through gene-environment interactions with minimum smoking.

AB - Background: α1-Antitrypsin deficiency is caused by rare pathogenic variants in SERPINA1, the strongest genetic risk factor for chronic obstructive pulmonary disease. Few studies have evaluated the effects of SERPINA1 variation on asthma severity accounting for critical gene-by-environment interactions with smoking. Objective: To characterize the influence of SERPINA1 variation on asthma severity. Methods: DNA samples from 847 non-Hispanic White and 446 African American participants from the Severe Asthma Research Program underwent SERPINA1 resequencing to identify rare variants. An independent population of 1955 individuals with asthma and α1-antitrypsin concentrations from a Cleveland Clinic Health System (CCHS) database were evaluated for severity measures. Results: In White participants, a history of minimum smoking significantly interacted with SERPINA1 low-to-rare frequency variation to determine risk for asthma-related health care utilization. This was attributed to protease inhibitor type Z heterozygotes (MZ, N = 11), who had a higher frequency of emergency department (ED) visits (6 [54.5%] MZ heterozygotes, odds ratio [OR] = 7.60, 95% confidence interval [CI] = 1.71-39.7, P = .010), hospitalization (5 [45.5%], OR = 16.1, 95% CI = 2.64-150.4, P = .0050) in the past year, and lifetime intensive care unit (ICU) admissions (6 [54.5%], OR = 12.5, 95% CI = 2.44-75.6, P = .0032) compared with 146 individuals without SERPINA1 variants (30 [20.5%] reporting ED visits, 17 [11.6%] hospitalization, and 15 [10.3%] ICU admission). SERPINA1 variant-by–ever smoking interactions in African American participants for ED visits (P = .069) were related to 4 of 6 compound heterozygotes reporting an ED visit. In CCHS, α1-antitrypsin concentrations were inversely associated with moderate-to-severe asthma risk (OR = 0.97 per 10 mg/dL increase in α1-antitrypsin, 95% CI = 0.94-0.99, P = .010) and exacerbations (OR = 0.84 per 10 mg/dL, 95% CI = 0.76-0.94, P = .002). Conclusions: SERPINA1 variation and α1-antitrypsin concentrations impact asthma severity through gene-environment interactions with minimum smoking.

KW - Alpha1-antitrypsin

KW - Asthma

KW - Exacerbations

KW - Genetics

KW - Lung function

KW - Rare variant

KW - SERPINA1

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DO - 10.1016/j.jaip.2025.01.039

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