TY - JOUR T1 - The Undiagnosed Disease Burden Associated with Alpha-1 Antitrypsin Deficiency Genotypes JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.01441-2020 SP - 2001441 AU - Tomoko Nakanishi AU - Vincenzo Forgetta AU - Tomohiro Handa AU - Toyohiro Hirai AU - Vincent Mooser AU - Mark G. Lathrop AU - William O.C.M. Cookson AU - J. Brent Richards Y1 - 2020/01/01 UR - http://erj.ersjournals.com/content/early/2020/06/25/13993003.01441-2020.abstract N2 - 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 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 FEV1/FVC was used to evaluate variable penetrance of PI*ZZ.Amongst 458 164 European-ancestry participants in UK Biobank, 140 had the PI*ZZ genotype and only 9 of them (6.4%, 95%CI: 3.4%–11.7%) 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 diagnoses (OR: 7.8, 95%CI 2.5–24.6) 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 amongst smokers. PheWAS demonstrated associations with increased odds of empyema, pneumothorax, cachexia, polycythemia, aneurysm, and pancreatitis. PRS and PI*ZZ were independently associated with FEV1/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).The important under-diagnosis of AATD, whose outcomes are partially preventable through smoking cession, could be improved through genotype-guided diagnosis.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Nakanishi has nothing to disclose.Conflict of interest: Dr. Forgetta has nothing to disclose.Conflict of interest: Tomohiro Handa is in the employ of the Collaborative Research Laboratory funded by Teijin Pharma Co., Ltd..Conflict of interest: Dr. 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: Dr. Mooser has nothing to disclose.Conflict of interest: Dr. Lathrop has nothing to disclose.Conflict of interest: Dr. Cookson has nothing to disclose.Conflict of interest: Dr. Richards has nothing to disclose. ER -