Alluhibi, Reem;
Baradwaaj, Shashank;
Heyer-Chauhan, Nina;
Marshall, Aileen;
Lomas, David A;
Salama, Alan D;
Hurst, John R;
(2025)
Alpha-1 antitrypsin deficiency and granulomatosis with polyangiitis: a systematic review and meta-analysis.
European Respiratory Review
, 34
(178)
, Article 250088. 10.1183/16000617.0088-2025.
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Abstract
INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder characterised by low circulating levels of alpha-1 antitrypsin (AAT) protein, a key inhibitor of neutrophil elastase and proteinase 3 (PR3) which is also the main autoantigen in granulomatosis with polyangiitis (GPA). This systematic review examines the association between AATD and GPA. METHODS: A systematic search of PubMed, Embase, Cochrane, EBSCO Medline and Scopus (December 2024) identified studies on AATD and GPA. Data extraction and quality assessment followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A random-effects meta-analysis was conducted to calculate pooled odds ratios and assess heterogeneity. RESULTS: 23 studies (9634 individuals) met inclusion criteria. The Z-allele prevalence was 11.65% in GPA compared to 3.29% in controls and the S-allele prevalence was 10.8% in GPA compared to 5.26% in controls. Among 1755 individuals with GPA across 10 studies that provided specific genotype data, 22 (1.25%) were homozygous for the Z-allele. Meta-analysis showed that Z-allele carriers had 3.11 times higher odds of developing GPA (eight studies; 95% CI 2.43–3.9; I2: 0%). CONCLUSION: This meta-analysis reinforces the link between AATD and GPA, particularly in carriers of the Z-allele, supporting the role of PR3 dysregulation in GPA pathogenesis.
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