Evaluation of Alpha1 Antitrypsin Deficiency-Associated Mutations in People with Cystic Fibrosis

TL;DR

This study finds that alpha1 antitrypsin deficiency mutations are common in cystic fibrosis patients and may affect their health outcomes.

Contribution

The study identifies specific AATD mutations in CF patients and proposes optimal cutoffs for serum AAT levels to detect these mutations.

Findings

15.7% of CF patients had at least one AATD mutation.

AAT levels of 129 mg/dL and 99.5 mg/dL were optimal cutoffs for detecting AATD mutations in the overall cohort and excluding PI*MS cases, respectively.

AATD mutations were associated with mild exacerbations during follow-up.

Abstract

Background: Recent hypotheses suggest that mutations associated with alpha1 antitrypsin (AAT) deficiency (AATD) may influence the clinical presentation and progression of cystic fibrosis (CF). This study employs a longitudinal design to determine the prevalence of AATD mutations and assess their impact on CF. Methods: The study Finding AAT Deficiency in Obstructive Lung Diseases: Cystic Fibrosis (FADO-CF) is a retrospective cohort study evaluating people with CF from November 2020 to February 2024. On the date of inclusion, serum levels of AAT were measured and a genotyping of 14 mutations associated with AATD was performed. Historical information, including data on exacerbations, microbiological sputum isolations, and lung function, was obtained from the medical records, aiming at a temporal lag of 10 years. Results: The sample consisted of 369 people with CF (40.9% pediatrics). Of these, 58 (15.7%) cases presented at least one AATD mutation. The AATD allelic combinations identified were PI*MS in 47 (12.7%) cases, PI*MZ in 5 (1.4%) cases, PI*SS in 3 (0.8%) cases, PI*SZ in 2 (0.5%) cases, and PI*M/Plowell in 1 (0.3%) case. The optimal cutoff value for AAT levels to detect AATD-associated mutation carriers was 129 mg/dL in the overall cohort (sensitivity of 73.0%; specificity 69.2%) and 99.5 mg/dL when excluding PI*MS cases (sensitivity 98.0%; specificity 90.9%), highlighting the need for lower thresholds in clinically severe genotypes to improve case detection. The number of mild exacerbations during the follow-up appeared to be associated with AATD mutations. Conclusions: AATD mutations are prevalent in CF and may impact certain clinical outcomes. If systematic screening was to be planned, we recommend considering the proposed cut-off points to select the population for genetic studies.

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