Abstract
DNA sequencing of the SERPINA1 gene to detect α1-antitrypsin (AAT) deficiency (AATD) may provide a better appreciation of the individual and cumulative impact of genetic variants on AAT serum levels and COPD phenotypes.
AAT serum level and DNA sequencing of the coding regions of SERPINA1 were performed in 1359 participants of the Canadian Cohort Obstructive Lung Disease (CanCOLD) study. Clinical assessment for COPD included questionnaires, pulmonary function testing and computed tomography (CT) imaging. Phenotypes were tested for association with SERPINA1 genotypes collated into four groups: normal (MM), mild (MS and MI), intermediate (heterozygote MZ, non-S/non-Z/non-I, compound IS, and homozygote SS) and severe (ZZ and SZ) deficiency. Smoking strata and MZ-only analyses were also performed.
34 genetic variants were identified including 25 missense mutations. Overall, 8.1% of alleles in this Canadian cohort were deficient and 15.5% of 1359 individuals were carriers of at least one deficient allele. Four AATD subjects were identified and had statistically lower diffusion capacity and greater CT-based emphysema. No COPD phenotypes were associated with mild and intermediate AATD in the overall cohort or stratified by smoking status. MZ heterozygotes had similar CT-based emphysema, but lowered diffusion capacity compared with normal and mild deficiency.
In this Canadian population-based cohort, comprehensive genetic testing for AATD reveals a variety of deficient alleles affecting 15.5% of subjects. COPD phenotype was demonstrated in severe deficiency and MZ heterozygotes. This study shows the feasibility of implementing a diagnostic test for AATD using DNA sequencing in a large cohort.
Abstract
15.5% of subjects in this Canadian cohort were carriers of at least one deficient allele affecting alpha-1 antitrypsin serum levels, but only genotypes resulting in severe deficiency and MZ heterozygotes were associated with COPD phenotypes https://bit.ly/3ekozCf
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.02628-2020
This article has supplementary material available from erj.ersjournals.com
Author contributions: Y. Bossé and J. Bourbeau conceived the study, have full access to the data, and take responsibility for the integrity of the data and article. N. Gaudreault and C. Henry performed the DNA sequencing. S. Thériault measured the AAT serum levels. M. Kirby, F. Maltais W. Tan and J. Bourbeau contributed to the study design, performed clinical recruitment and phenotyping of patients. P.Z. Li and Y. Bossé performed data analysis. N. Gupta, J. Bourbeau and Y. Bossé wrote the manuscript. N. Gaudreault, S. Thériault, M. Kirby, F. Maltais and W. Tan edited the manuscript for intellectual content. All authors approved the final manuscript.
Conflict of interest: N. Gupta has nothing to disclose.
Conflict of interest: N. Gaudreault has nothing to disclose.
Conflict of interest: S. Thériault has nothing to disclose.
Conflict of interest: P.Z. Li has nothing to disclose.
Conflict of interest: C. Henry has nothing to disclose.
Conflict of interest: M. Kirby is a consultant for Vida Diagnostics Inc., outside the submitted work.
Conflict of interest: F. Maltais reports grants from AstraZeneca and GlaxoSmithKline, Boehringer Ingelheim, GSK, Sanofi and Novartis during the conduct of this study, and personal fees for serving on speaker bureaus and consultation panels from Boehringer Ingelheim, Grifols and Novartis, outside the submitted work; and is financially involved with Oxynov, a company which is developing an oxygen delivery system.
Conflict of interest: W. Tan reports grants from Canadian Institute of Heath Research (CIHR/Rx&D Collaborative Research Program Operating Grants- 93326) with industry partners AstraZeneca Canada Ltd, Boehringer Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd, Merck, Novartis Pharma Canada Inc., Nycomed Canada Inc. and Pfizer Canada Ltd, during the conduct of the study.
Conflict of interest: J. Bourbeau reports grants from CIHR, Canadian Respiratory Research Network (CRRN), Foundation of the MUHC and Aerocrine, personal fees for consultancy and lectures from Canadian Thoracic Society and CHEST, grants and personal fees for advisory board work and lectures from AstraZeneca, Boehringer Ingelheim, Grifols, GlaxoSmithKline, Novartis and Trudell, outside the submitted work.
Conflict of interest: Y. Bossé reports grants from Grifols Canada Ltd, during the conduct of the study; personal fees for lectures from Grifols Canada Ltd, outside the submitted work.
Support statement: This work was supported by Grifols Canada Ltd, the Fondation de l'Institut universitaire de cardiologie et de pneumologie de Québec, the Respiratory Health Network of the Fonds de recherche Québec – Santé (FRQS), and the Canadian Institutes of Health Research (MOP - 123369). The Canadian Cohort Obstructive Lung Disease (CanCOLD) study is currently funded by the Canadian Respiratory Research Network (CRRN); industry partners: AstraZeneca Canada Ltd; Boehringer Ingelheim Canada Ltd; GlaxoSmithKline Canada Ltd; Novartis. Researchers at RI-MUHC Montreal and Icapture Centre Vancouver lead the project. Previous funding partners are the CIHR (CIHR/Rx&D Collaborative Research Program Operating Grants- 93326); the RHN of the FRQS; industry partners: Almirall; Merck Nycomed; Pfizer Canada Ltd; and Theratechnologies. S. Thériault holds a Junior 1 Clinical Research Scholar award from the FRQS. M. Kirby holds a Canada Research Chair in Quantitative Imaging. F. Maltais holds a GSK Research Chair on COPD at Université Laval. J. Bourbeau holds a GSK/CIHR Research Chair on COPD at McGill University. Y. Bossé holds a Canada Research Chair in Genomics of Heart and Lung Diseases. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received April 1, 2020.
- Accepted May 20, 2020.
- Copyright ©ERS 2020
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