Abstract
DNA sequencing of the SERPINA1 gene to detect alpha-1 antitrypsin deficiency (AATD) may provide a better appreciation of the individual and cumulative impact of genetic variants on alpha-1 antitrypsin (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.
Thirty-four 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 to 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.
Footnotes
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Conflict of interest: Dr. Gupta has nothing to disclose.
Conflict of interest: Dr. Gaudreault has nothing to disclose.
Conflict of interest: Dr. Thériault has nothing to disclose.
Conflict of interest: Dr. Li has nothing to disclose.
Conflict of interest: Dr. Henry has nothing to disclose.
Conflict of interest: Dr. Kirby reports other from Vida Diagnostics Inc., outside the submitted work.
Conflict of interest: FM 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. He is financially involved with Oxynov, a company which is developing an oxygen delivery system.
Conflict of interest: Dr. Tan reports grants from Canadian Institute of Heath Research (CIHR/Rx&D Collaborative Research Program Operating Grants- 93326) with industry partners Astra Zeneca Canada Ltd., Boehringer-Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd, Merck, Novartis Pharma Canada Inc., Nycomed Canada Inc., Pfizer Canada Ltd., during the conduct of the study.
Conflict of interest: Dr. Bourbeau reports grants from CIHR, grants from Canadian Respiratory Research Network (CRRN), personal fees from Canadian Thoracic Society, personal fees from CHEST, grants from Foundation of the MUHC, grants from Aerocrine, grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Grifols, grants and personal fees from GlaxoSmithKline, grants and personal fees from Novartis, grants and personal fees from Trudell, outside the submitted work.
Conflict of interest: Dr. Bossé reports grants from Grifols Canada Ltd., during the conduct of the study; personal fees from Grifols Canada Ltd., outside the submitted work.
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- Received April 1, 2020.
- Accepted May 20, 2020.
- Copyright ©ERS 2020