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. 2025 Jul;13(7):1634-1646.e7.
doi: 10.1016/j.jaip.2025.01.039. Epub 2025 Feb 13.

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

Victor E Ortega  1 , Vickram Tejwani  2 , Abhishek Kumar Shrivastav  3 , Sara Pasha  4 , Joe G Zein  3 , Meher Boorgula  5 , Mario Castro  6 , Loren Denlinger  7 , Serpil C Erzurum  8 , John V Fahy  9 , Elliot Israel  10 , Nizar N Jarjour  7 , Bruce Levy  10 , David Mauger  11 , Wendy C Moore  12 , Sally E Wenzel  13 , Prescott Woodruff  14 , Gregory A Hawkins  15 , Eugene R Bleecker  3 , Deborah A Meyers  3 ; NHLBI Severe Asthma Research Program (SARP)
Affiliations

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

Victor E Ortega et al. J Allergy Clin Immunol Pract. 2025 Jul.

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.

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