Alpha-1 antitrypsin deficiency and granulomatosis with polyangiitis: a systematic review and meta-analysis

Reem Alluhibi; Shashank Baradwaaj; Nina Heyer-Chauhan; Aileen Marshall; David A Lomas; Alan D Salama; John R Hurst

doi:10.1183/16000617.0088-2025

Alpha-1 antitrypsin deficiency and granulomatosis with polyangiitis: a systematic review and meta-analysis

Eur Respir Rev. 2025 Oct 22;34(178):250088. doi: 10.1183/16000617.0088-2025. Print 2025 Oct.

Authors

Reem Alluhibi^{1

2

3}, Shashank Baradwaaj⁴, Nina Heyer-Chauhan⁴, Aileen Marshall⁵, David A Lomas⁴, Alan D Salama⁶, John R Hurst⁴

Affiliations

¹ UCL Respiratory, University College London, London, UK reem.alluhibi.23@ucl.ac.uk.
² Department of Respiratory Care, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.
³ King Abdullah International Medical Research Centre, Jeddah, Saudi Arabia.
⁴ UCL Respiratory, University College London, London, UK.
⁵ Hepatology, Royal Free London NHS Foundation Trust, London, UK.
⁶ UCL Centre for Kidney and Bladder Health, Royal Free Hospital, London, UK.

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.

Publication types

Systematic Review
Meta-Analysis

MeSH terms

Genetic Predisposition to Disease
Granulomatosis with Polyangiitis* / diagnosis
Granulomatosis with Polyangiitis* / epidemiology
Granulomatosis with Polyangiitis* / genetics
Humans
Phenotype
Prevalence
Risk Assessment
Risk Factors
alpha 1-Antitrypsin Deficiency* / diagnosis
alpha 1-Antitrypsin Deficiency* / epidemiology
alpha 1-Antitrypsin Deficiency* / genetics
alpha 1-Antitrypsin* / genetics

Substances

alpha 1-Antitrypsin