Victor E Ortega, Vickram Tejwani, Abhishek Kumar Shrivastav, Sara Pasha, Joe G Zein, Meher Boorgula, Mario Castro, Loren Denlinger, Serpil C Erzurum, John V Fahy, Elliot Israel, Nizar N Jarjour, Bruce Levy, David Mauger, Wendy C Moore, Sally E Wenzel, Prescott Woodruff, Gregory A Hawkins, Eugene R Bleecker, Deborah A Meyers
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引用次数: 0
Abstract
Background: α1-antitrypsin deficiency is caused by rare pathogenic variants in SERPINA1, the strongest genetic risk factor for COPD. 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 whites and 446 African Americans from the Severe Asthma Research Program underwent SERPINA1 resequencing to identify rare variants. An independent population of 1,955 individuals with asthma and α1-antitrypsin concentrations from a Cleveland Clinic Health System (CCHS) database were evaluated for severity measures.
Measurements and main results: In whites, a history of minimum smoking significantly interacted with SERPINA1 low-to-rare frequency variation to determine risk for asthma-related healthcare utilization. This was attributed to PI type Z heterozygotes (MZ, N=11) who had a higher frequency of ED visits (6 [54.5%] MZ heterozygotes, OR=7.60, 95%CI=1.71-39.7, p=0.010), hospitalization (5 [45.5%], OR=16.1, 95%CI=2.64-150.4, p=0.0050) in the past year, and lifetime ICU admissions (6 [54.5%], OR=12.5, 95%CI=2.44-75.6, p=0.0032) compared to 146 individuals without SERPINA1 variants (30 [20.5%] reporting ED visits, 17 [11.6%] hospitalization, 15 [10.3%] ICU admission). SERPINA1 variant-ever smoking interactions in African Americans for ED visits (p=0.069) related to four of six 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=0.010) and exacerbations (OR=0.84 per 10 mg/dL, 95%CI=0.76-0.94, p=0.002).
Conclusions: SERPINA1 variation and α1-antitrypsin concentrations impact asthma severity through gene-environment interactions with minimum smoking.
期刊介绍：
JACI: In Practice is an official publication of the American Academy of Allergy, Asthma & Immunology (AAAAI). It is a companion title to The Journal of Allergy and Clinical Immunology, and it aims to provide timely clinical papers, case reports, and management recommendations to clinical allergists and other physicians dealing with allergic and immunologic diseases in their practice. The mission of JACI: In Practice is to offer valid and impactful information that supports evidence-based clinical decisions in the diagnosis and management of asthma, allergies, immunologic conditions, and related diseases.
This journal publishes articles on various conditions treated by allergist-immunologists, including food allergy, respiratory disorders (such as asthma, rhinitis, nasal polyps, sinusitis, cough, ABPA, and hypersensitivity pneumonitis), drug allergy, insect sting allergy, anaphylaxis, dermatologic disorders (such as atopic dermatitis, contact dermatitis, urticaria, angioedema, and HAE), immunodeficiency, autoinflammatory syndromes, eosinophilic disorders, and mast cell disorders.
The focus of the journal is on providing cutting-edge clinical information that practitioners can use in their everyday practice or to acquire new knowledge and skills for the benefit of their patients. However, mechanistic or translational studies without immediate or near future clinical relevance, as well as animal studies, are not within the scope of the journal.
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