The Undiagnosed Disease Burden Associated with Alpha-1 Antitrypsin Deficiency Genotypes
- Tomoko Nakanishi1,2,3,4,5,
- Vincenzo Forgetta2,
- Tomohiro Handa6,
- Toyohiro Hirai4,
- Vincent Mooser1,7,
- Mark G. Lathrop8,
- William O.C.M. Cookson9,10 and
- J. Brent Richards1,2,11⇑
- 1Department of Human Genetics, McGill University, Montréal, Québec, Canada
- 2Centre for Clinical Epidemiology, Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal, Québec, Canada
- 3Kyoto–McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- 4Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- 5Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
- 6Department of Advanced Medicine for Respiratory Failure, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- 7Canada Excellence Research Chair in Genomic Medicine, McGill University, Montréal, Québec, Canada
- 8McGill University and Genome Québec Innovation Centre, Montréal, Québec, Canada
- 9National Heart and Lung Institute, Imperial College London, London, United Kingdom
- 10Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom
- 11Division of Endocrinology, Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, Jewish General Hospital, McGill University, Montréal, Québec, Canada
- Correspondene: J. Brent Richards, MD, MSc, Professor of Medicine, William Dawson Scholar / FRQS Clinical Research Scholar, McGill University, Senior Lecturer, King's College London (Honorary), Contact: Pavillon H-413, Jewish General Hospital, 3755 Cote Ste Catherine, Montréal, Québec, Canada, H3T 1E2. E-mail: brent.richards{at}mcgill.ca www.mcgill.ca/genepi
Abstract
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.
Footnotes
This 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.
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- Received April 27, 2020.
- Accepted June 25, 2020.
- Copyright ©ERS 2020