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Historically, evidence has been lacking to support the concept that heterozygotes are at increased risk for liver and\/or lung complications compared to individuals homozygous for the M allele. However, growing evidence suggests that inheritance of a single Z allele increases the risk of disease in some individuals. The Alpha-1 Foundation convened a workshop on October 27, 2023, in Bethesda, Maryland that included stakeholders from the research, pharmaceutical, and patient communities. The focus of the meeting was to describe and assess what is known about the relative risks of liver and\/or lung disease for heterozygotes and to identify future avenues of research into disease mechanisms and clinical phenotypes in MZ heterozygotes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Population-based and family studies of individuals heterozygous for the AATD Z risk allele demonstrate that a proportion of these individuals have relatively higher risk for lung or liver disease than do individuals harboring no variants in\n                      <jats:italic>SERPINA1<\/jats:italic>\n                      . Included are studies identifying increased rates of chronic obstructive pulmonary disease (COPD) among MZ and SZ smokers compared to MM individuals with similar histories of smoke exposure. Evidence collected from human macrophages, cellular and mouse models of AATD, and explanted tissue from AATD patients provides clues to the disease mechanisms associated with Z heterozygosity. Early-stage research is focused on identifying the proportion of MZ individuals who might be at increased risk of disease and determining whether treatment strategies in current use or under investigation for ZZ patients might be appropriate and beneficial for Z heterozygotes. Participants discussed clinical trials design and infrastructure needed to study the AATD heterozygous population.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Evidence at this time suggests modest increased risk among Z heterozygotes as a result of carrying a single Z gene. Associated risk of this population to develop either liver or lung disease is modified by genetic and environmental factors. Focused clinical trials are needed before using treatments beneficial for homozygous Z individuals in this population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial number<\/jats:title>\n                    <jats:p>Not applicable.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-026-04283-9","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T11:39:21Z","timestamp":1775648361000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Z variant heterozygosity in alpha-1 antitrypsin deficiency: disease risk and treatment implications"],"prefix":"10.1186","volume":"21","author":[{"given":"Craig P.","family":"Hersh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey H.","family":"Teckman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Strnad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Hakim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom\u00e1s P.","family":"Carroll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian P.","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Auyon J.","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Barjaktarevic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noel G.","family":"McElvaney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph E.","family":"Kaserman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Lomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlie","family":"Strange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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J.T. reports grant support from Arrowhead, Congruence, BioMarin, Bridge Bio, Intellia, Korro Bio, Logi Bio, Takeda, UniQure, Vertex, Beam Therapeutics, and Inhibrx as well as consulting fees from Congruence, BioMarin, Bridge Bio, Korro Bio, Logic Bio, Takeda, UniQure, and Beam Therapeutics. P.S. reports grant support from DFG Arrowhead, Vertex, CSL Behring, GSK, Intellia, Dicerna, Takeda, Novo Nordisk, and Biomarin; consulting fees, honoraria, or other support from Albireo, CSL Behring, Intellia, Takeda, Grifols, Dicrena, Sanofi, Falk Foundation, Grifols, Vertex, and Gilead. I.B. reports grant support from Theravance and Viatris, Aerogen, Takeda; consulting feels or honoraria from Astra Zeneca, Sanofi, Regeneron, Grifols, Verona Pharma, Inhibrx, and Takeda. N.G.M. serves on the Board of Directors of the Alpha-1 Foundation and reports grant support from Grifols and CSL Behring; consulting fees or honoraria from Intellia, Vertex, Inhibrx, Takeda, Dicerna, Centessa, CSL behring. D.L. reports grant support, royalties\/licenses, and consulting fees from Biomarin as well as compensation for grant review from Grifols. C.S. serves as medical director of AlphaNet and resports grants support from Adverum, Arrowhead, AstraZeneca, CSA Medical, Dicerna, Grifols, Krystal, Nuvaira, OCI, Pandorum, Takeda and Vertex as well as consulting fees from Astra Zeneca, CSL Behring, Morair, Pulmanage, UpToDate, and Vertex.B.D. reports grant support from Vertex and consulting fees from Takeda. V.C. serves on the Board of Directors of the Alpha-1 Foundation and reports grant support from Takeda, Vertex, and Arrowhead as well as consulting fees from Takeda. A.W. serves as Scientific Director to the Alpha-1 Foundation and reports current or recent prior grant support from Grifols, and the Alpha-1 Foundation. Other authors report no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"136"}}