{"doi":"10.17615/gg0x-6064","title":"The effects of rare SERPINA1 variants on lung function and emphysema in SPIROMICS","abstract":"Rationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A,member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial. Objectives: To comprehensively evaluate the effects of rare SERPINA1 variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations. Methods: DNA samples from 1,693 non-Hispanic white individuals, 385 African Americans, and 90 Hispanics with >20 pack-years smoking were resequenced for the identification of rare variants (allele frequency,0.05) in 16.9 kB of SERPINA1. Measurements and Main Results: White PI Z heterozygotes confirmed by sequencing (MZ; n = 74) had lower postbronchodilator FEV1 (P = 0.007), FEV1/FVC (P = 0.003), and greater computed tomography-based emphysema (P = 0.02) compared with 1,411 white individuals without PI Z, S, or additional rare variants denoted as VR. PI Z-containing compound heterozygotes (ZS/ZVR; n = 7) had lower FEV1/FVC (P = 0.02) and forced expiratory flow, midexpiratory phase (P = 0.009). Nineteen white heterozygotes for five non-S/Z coding variants associated with lower alpha-1 antitrypsin had greater computed tomography-based emphysema compared with those without rare variants. In African Americans, a 59 untranslated region insertion (rs568223361) was associated with lower alpha-1 antitrypsin and functional small airway disease (P = 0.007). Conclusions: In this integrative deep sequencing study of SERPINA1 with alpha-1 antitrypsin concentrations in a heavy smoker and chronic obstructive pulmonary disease cohort, we confirmed the effects of PI Z heterozygote and compound heterozygote genotypes. We demonstrate the cumulative effects of multiple SERPINA1 variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of SERPINA1 variation associated with respiratory disease in at-risk smokers.","journal":"eScholarship (California Digital Library)","year":2021,"id":203167,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9632,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":6692,"name":"C. Cooper","orcid":null,"position":1,"is_corresponding":false},{"id":365720,"name":"M.K. Han","orcid":null,"position":2,"is_corresponding":false},{"id":140348,"name":"R. Paine","orcid":null,"position":3,"is_corresponding":false},{"id":549309,"name":"A. Laederach","orcid":null,"position":4,"is_corresponding":false},{"id":453946,"name":"C. Pirozzi","orcid":null,"position":5,"is_corresponding":false},{"id":453928,"name":"I. Barjaktarevic","orcid":null,"position":6,"is_corresponding":false},{"id":784375,"name":"G.A. Hawkins","orcid":null,"position":7,"is_corresponding":false},{"id":365730,"name":"W.K. O apos Neal","orcid":null,"position":8,"is_corresponding":false},{"id":453940,"name":"V.E. Ortega","orcid":null,"position":9,"is_corresponding":false},{"id":365724,"name":"P.G. Woodruff","orcid":null,"position":10,"is_corresponding":false},{"id":784376,"name":"P.J. Grayeski","orcid":null,"position":11,"is_corresponding":false},{"id":365740,"name":"E.C. Kleerup","orcid":null,"position":12,"is_corresponding":false},{"id":784377,"name":"E. Ampleford","orcid":null,"position":13,"is_corresponding":false},{"id":365727,"name":"E.A. Hoffman","orcid":null,"position":14,"is_corresponding":false},{"id":140351,"name":"F.J. Martinez","orcid":null,"position":15,"is_corresponding":false},{"id":453937,"name":"D. Couper","orcid":null,"position":16,"is_corresponding":false},{"id":365718,"name":"R.G. Barr","orcid":null,"position":17,"is_corresponding":false},{"id":365738,"name":"R.E. Kanner","orcid":null,"position":18,"is_corresponding":false},{"id":365723,"name":"S.I. Rennard","orcid":null,"position":19,"is_corresponding":false},{"id":365721,"name":"D.A. Meyers","orcid":null,"position":20,"is_corresponding":false},{"id":784378,"name":"L. Lackey","orcid":null,"position":21,"is_corresponding":false},{"id":599849,"name":"X. Li","orcid":"0009-0006-3049-3186","position":22,"is_corresponding":false},{"id":365733,"name":"E.R. Bleecker","orcid":null,"position":23,"is_corresponding":false},{"id":453942,"name":"S.P. Peters","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:51:14.206397Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}