Imperial College London
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Professor William Cookson

Faculty of Medicine, National Heart & Lung Institute

Professor of Genomic Medicine
 
 
 
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Contact

 

+44 (0)20 7594 2943w.cookson

 
 
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Location

 

400Guy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Citation

BibTex format

@article{Nakanishi:2020:10.1183/13993003.01441-2020,
author = {Nakanishi, T and Forgetta, V and Handa, T and Hirai, T and Mooser, V and Lathrop, GM and Cookson, WOCM and Richards, JB},
doi = {10.1183/13993003.01441-2020},
journal = {European Respiratory Journal},
pages = {1--11},
title = {The undiagnosed disease burden associated with alpha-1 antitrypsin deficiency genotypes},
url = {http://dx.doi.org/10.1183/13993003.01441-2020},
volume = {56},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Alpha-1 antitrypsin deficiency (AATD), mainly due to the PIZZ 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 PIZZ individuals through genotyping could improve health outcomes.We examined the frequency of the PIZZ 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 1s (FEV1)/forced vital capacity (FVC) ratio was used to evaluate variable penetrance of PIZZ.Among 458164 European-ancestry participants in UK Biobank, 140 had the PIZZ genotype and only nine (6.4%, 95% CI 3.4–11.7%) of them were diagnosed with AATD. Those with PIZZ 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 PIMM (wildtype) (n=398424). These associations were stronger among smokers. PheWAS demonstrated associations with increased odds of empyema, pneumothorax, cachexia, polycythaemia, aneurysm and pancreatitis. Polygenic risk score and PIZZ 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, respectively).The important underdiagnosis of AATD, whose outcomes are partially preventable through smoking cession, could be improved through genotype-guided diagnosis.
AU  - Nakanishi,T
AU  - Forgetta,V
AU  - Handa,T
AU  - Hirai,T
AU  - Mooser,V
AU  - Lathrop,GM
AU  - Cookson,WOCM
AU  - Richards,JB
DO  - 10.1183/13993003.01441-2020
EP  - 11
PY  - 2020///
SN  - 0903-1936
SP  - 1
TI  - The undiagnosed disease burden associated with alpha-1 antitrypsin deficiency genotypes
T2  - European Respiratory Journal
UR  - http://dx.doi.org/10.1183/13993003.01441-2020
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000620192200016&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://erj.ersjournals.com/content/56/6/2001441
UR  - http://hdl.handle.net/10044/1/91479
VL  - 56
ER  -
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