{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T18:12:37Z","timestamp":1789668757228,"version":"4.0.1"},"posted":{"date-parts":[[2026,9,14]]},"group-title":"Respiratory Medicine","reference-count":37,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["K08 HL168348"],"award-info":[{"award-number":["K08 HL168348"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/04t31bx63","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Sarcopenia 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We performed a retrospective analysis of 487,207 participants in the UK Biobank with available\n                    <jats:italic>SERPINA1<\/jats:italic>\n                    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\u2081% 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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Compared 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 (\u223c2.6%) of this association.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions.<\/jats:title>\n                  <jats:p>\n                    The\n                    <jats:italic>SERPINA1<\/jats:italic>\n                    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.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.12.26362905","type":"posted-content","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:10:15Z","timestamp":1789449015000},"source":"Crossref","is-referenced-by-count":0,"title":["The Alpha-1 Antitrypsin Z-allele associates with sarcopenia in the UK Biobank"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1959-9773","authenticated-orcid":false,"given":"Amy","family":"Attaway","sequence":"first","affiliation":[{"name":"Departments of Pulmonary Medicine, Cleveland Clinic, Cleveland, Ohio"},{"name":"Genomic Sciences and Systems Biology, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"Serban","sequence":"additional","affiliation":[{"name":"Departments of Medicine\/ Division of Pulmonary, Critical Care, Sleep Medicine and Molecular Genetics and Microbiology, University of Florida. Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shovan","family":"Dutta","sequence":"additional","affiliation":[{"name":"Genomic Sciences and Systems Biology, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umur","family":"Hatipo\u011flu","sequence":"additional","affiliation":[{"name":"Departments of Pulmonary Medicine, Cleveland Clinic, Cleveland, Ohio"},{"name":"Critical Care, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe","family":"Zein","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Medicine, Department of Medicine. Mayo Clinic Arizona. Scottsdale, AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Bazeley","sequence":"additional","affiliation":[{"name":"Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kyriakidou","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Medicine, Department of Medicine. Mayo Clinic Arizona. Scottsdale, AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Dawson","sequence":"additional","affiliation":[{"name":"Genomic Sciences and Systems Biology, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Ruvuna","sequence":"additional","affiliation":[{"name":"Departments of Pulmonary Medicine, Cleveland Clinic, Cleveland, Ohio"},{"name":"Genomic Sciences and Systems Biology, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Chad Wade","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham (UAB). Birmingham, AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vickram","family":"Tejwani","sequence":"additional","affiliation":[{"name":"Departments of Pulmonary Medicine, Cleveland Clinic, Cleveland, Ohio"},{"name":"Genomic Sciences and Systems Biology, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Bon","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care, Allergy, and Immunologic Diseases, Wake Forest University School of Medicine. Winston-Salem, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Michael Wells","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham (UAB). Birmingham, AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Ortega","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Medicine, Department of Medicine. Mayo Clinic Arizona. 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