The Alpha-1 Antitrypsin Z-allele associates with sarcopenia in the UK Biobank

Abstract

BackgroundSarcopenia is common in chronic obstructive pulmonary disease (COPD) and contributes to adverse outcomes. Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of COPD, but its impact on skeletal muscle remains to be determined.

MethodsWe performed a retrospective analysis of 487,207 participants in the UK Biobank with available SERPINA1 genotyping. Associations between AAT genotypes and measures of skeletal muscle mass were determined using multivariable linear and logistic regression models. Models adjusted for age, sex, smoking status, genetic principal components, lung function (FEV% predicted), and liver fibrosis risk (FIB-4). We determined that the Z-allele was associated with sarcopenia and mortality using regression models and mediation analysis.

ResultsCompared with PI*MM individuals, carriers of the Z allele (PI*MZ, PI*SZ, PI*ZZ) demonstrated significantly lower fat free mass index (FFMI) and appendicular skeletal muscle index (ASMI), as well as higher odds of sarcopenia by binary definition. Associations persisted after adjustment for lung and liver function. A dose-dependent relationship was observed, with the greatest reductions in muscle mass and highest sarcopenia associated with PI*ZZ individuals (adjusted OR for FFMI-defined sarcopenia 2.02, 95% CI 1.16-3.32). Each additional Z allele was associated with increased mortality risk (adjusted OR 1.09, 95% CI 1.02-1.16), with sarcopenia mediating a modest proportion ([~]2.6%) of this association.

Conclusions.The SERPINA1 Z allele is associated with reduced muscle mass and increased risk for sarcopenia independent of lung and liver disease. Our findings expand the phenotypic spectrum of AATD-related diseases to include skeletal muscle as a modifiable target for intervention.

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BibTeX RIS

BibTeX

@misc{attaway2026alpha1,
  title = {{The Alpha-1 Antitrypsin Z-allele associates with sarcopenia in the UK Biobank}},
  author = {A. H. Attaway and K. Serban and S. Dutta and U. Hatipoglu and J. Zein and P. Bazeley and M. Kyriakidou and J. E. Dawson and L. Ruvuna and R. C. Wade and V. Tejwani and J. Bon and J. M. Wells and V. Ortega and J. K. Stoller and R. Bowler},
  howpublished = {medRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.12.26362905},
  url = {https://www.medrxiv.org/content/10.64898/2026.09.12.26362905v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - The Alpha-1 Antitrypsin Z-allele associates with sarcopenia in the UK Biobank
AU  - A. H. Attaway
AU  - K. Serban
AU  - S. Dutta
AU  - U. Hatipoglu
AU  - J. Zein
AU  - P. Bazeley
AU  - M. Kyriakidou
AU  - J. E. Dawson
AU  - L. Ruvuna
AU  - R. C. Wade
AU  - V. Tejwani
AU  - J. Bon
AU  - J. M. Wells
AU  - V. Ortega
AU  - J. K. Stoller
AU  - R. Bowler
PY  - 2026
DA  - 2026/09/12
PB  - medRxiv
DO  - 10.64898/2026.09.12.26362905
UR  - https://www.medrxiv.org/content/10.64898/2026.09.12.26362905v1
AB  - BackgroundSarcopenia is common in chronic obstructive pulmonary disease (COPD) and contributes to adverse outcomes. Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of COPD, but its impact on skeletal muscle remains to be determined.  MethodsWe performed a retrospective analysis of 487,207 participants in the UK Biobank with available SERPINA1 genotyping. Associations between AAT genotypes and measures of skeletal muscle mass were determined using multivariable linear and logistic regression models. Models adjusted for age, sex, smoking status, genetic principal components, lung function (FEV% predicted), and liver fibrosis risk (FIB-4). We determined that the Z-allele was associated with sarcopenia and mortality using regression models and mediation analysis.  ResultsCompared with PI*MM individuals, carriers of the Z allele (PI*MZ, PI*SZ, PI*ZZ) demonstrated significantly lower fat free mass index (FFMI) and appendicular skeletal muscle index (ASMI), as well as higher odds of sarcopenia by binary definition. Associations persisted after adjustment for lung and liver function. A dose-dependent relationship was observed, with the greatest reductions in muscle mass and highest sarcopenia associated with PI*ZZ individuals (adjusted OR for FFMI-defined sarcopenia 2.02, 95% CI 1.16-3.32). Each additional Z allele was associated with increased mortality risk (adjusted OR 1.09, 95% CI 1.02-1.16), with sarcopenia mediating a modest proportion ([~]2.6%) of this association.  Conclusions.The SERPINA1 Z allele is associated with reduced muscle mass and increased risk for sarcopenia independent of lung and liver disease. Our findings expand the phenotypic spectrum of AATD-related diseases to include skeletal muscle as a modifiable target for intervention.
ER  -

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