PMID- 32675199 OWN - NLM STAT- MEDLINE DCOM- 20210621 LR - 20210621 IS - 1399-3003 (Electronic) IS - 0903-1936 (Print) IS - 0903-1936 (Linking) VI - 56 IP - 6 DP - 2020 Dec TI - The undiagnosed disease burden associated with alpha-1 antitrypsin deficiency genotypes. LID - 10.1183/13993003.01441-2020 [doi] LID - 2001441 AB - Alpha-1 antitrypsin deficiency (AATD), mainly due to the PI*ZZ genotype in SERPINA1, is one of the most common inherited diseases. Since it is associated with a high disease burden and partially prevented by smoking cessation, identification of PI*ZZ individuals through genotyping could improve health outcomes.We examined the frequency of the PI*ZZ genotype in individuals with and without diagnosed AATD from UK Biobank, and assessed the associations of the genotypes with clinical outcomes and mortality. A phenome-wide association study (PheWAS) was conducted to reveal disease associations with genotypes. A polygenic risk score (PRS) for forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) ratio was used to evaluate variable penetrance of PI*ZZ.Among 458 164 European-ancestry participants in UK Biobank, 140 had the PI*ZZ genotype and only nine (6.4%, 95% CI 3.4-11.7%) of them were diagnosed with AATD. Those with PI*ZZ had a substantially higher odds of COPD (OR 8.8, 95% CI 5.8-13.3), asthma (OR 2.0, 95% CI 1.4-3.0), bronchiectasis (OR 7.3, 95%CI 3.2-16.8), pneumonia (OR 2.7, 95% CI 1.5-4.9) and cirrhosis (OR 7.8, 95% CI 2.5-24.6) diagnoses and a higher hazard of mortality (2.4, 95% CI 1.2-4.6), compared to PI*MM (wildtype) (n=398 424). These associations were stronger among smokers. PheWAS demonstrated associations with increased odds of empyema, pneumothorax, cachexia, polycythaemia, aneurysm and pancreatitis. Polygenic risk score and PI*ZZ were independently associated with FEV(1)/FVC <0.7 (OR 1.4 per 1-sd change, 95% CI 1.4-1.5 and OR 4.5, 95% CI 3.0-6.9, respectively).The important underdiagnosis of AATD, whose outcomes are partially preventable through smoking cession, could be improved through genotype-guided diagnosis. CI - Copyright (c)ERS 2020. FAU - Nakanishi, Tomoko AU - Nakanishi T AUID- ORCID: 0000-0001-9510-5646 AD - Dept of Human Genetics, McGill University, Montreal, QC, Canada. AD - Centre for Clinical Epidemiology, Dept of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada. AD - Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. AD - Dept of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. AD - Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan. FAU - Forgetta, Vincenzo AU - Forgetta V AUID- ORCID: 0000-0002-6061-4720 AD - Centre for Clinical Epidemiology, Dept of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada. FAU - Handa, Tomohiro AU - Handa T AUID- ORCID: 0000-0002-3378-6412 AD - Dept of Advanced Medicine for Respiratory Failure, Graduate School of Medicine, Kyoto University, Kyoto, Japan. FAU - Hirai, Toyohiro AU - Hirai T AD - Dept of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. FAU - Mooser, Vincent AU - Mooser V AD - Dept of Human Genetics, McGill University, Montreal, QC, Canada. AD - Canada Excellence Research Chair in Genomic Medicine, McGill University, Montreal, QC, Canada. FAU - Lathrop, G Mark AU - Lathrop GM AD - McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada. FAU - Cookson, William O C M AU - Cookson WOCM AUID- ORCID: 0000-0001-9551-4677 AD - National Heart and Lung Institute, Imperial College London, London, UK. AD - Royal Brompton and Harefield NHS Foundation Trust, London, UK. FAU - Richards, J Brent AU - Richards JB AUID- ORCID: 0000-0002-3746-9086 AD - Dept of Human Genetics, McGill University, Montreal, QC, Canada brent.richards@mcgill.ca. AD - Centre for Clinical Epidemiology, Dept of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada. AD - Division of Endocrinology, Depts of Medicine, Human Genetics, Epidemiology and Biostatistics, Jewish General Hospital, McGill University, Montreal, QC, Canada. LA - eng GR - MC_PC_17228/MRC_/Medical Research Council/United Kingdom GR - MC_QA137853/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201210 PL - England TA - Eur Respir J JT - The European respiratory journal JID - 8803460 RN - 0 (alpha 1-Antitrypsin) SB - IM MH - Cost of Illness MH - Genotype MH - Humans MH - *Pulmonary Disease, Chronic Obstructive/diagnosis/epidemiology/genetics MH - *Undiagnosed Diseases MH - alpha 1-Antitrypsin/genetics MH - *alpha 1-Antitrypsin Deficiency/complications/diagnosis/epidemiology PMC - PMC7726845 COIS- Conflict of interest: T. Nakanishi has nothing to disclose. Conflict of interest: V. Forgetta has nothing to disclose. Conflict of interest: T. Handa is in the employ of the Collaborative Research Laboratory funded by Teijin Pharma Co., Ltd. Conflict of interest: T. Hirai reports grants from The Intractable Respiratory Diseases and Pulmonary Hypertension Research Group, the Ministry of Health, Labor and Welfare, Japan, outside the submitted work. Conflict of interest: V. Mooser has nothing to disclose. Conflict of interest: G.M. Lathrop has nothing to disclose. Conflict of interest: W.O.C.M. Cookson has nothing to disclose. Conflict of interest: J.B. Richards has nothing to disclose. EDAT- 2020/07/18 06:00 MHDA- 2021/06/22 06:00 PMCR- 2020/12/10 CRDT- 2020/07/18 06:00 PHST- 2020/04/27 00:00 [received] PHST- 2020/06/25 00:00 [accepted] PHST- 2020/07/18 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2020/07/18 06:00 [entrez] PHST- 2020/12/10 00:00 [pmc-release] AID - 13993003.01441-2020 [pii] AID - ERJ-01441-2020 [pii] AID - 10.1183/13993003.01441-2020 [doi] PST - epublish SO - Eur Respir J. 2020 Dec 10;56(6):2001441. doi: 10.1183/13993003.01441-2020. Print 2020 Dec.