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Sequencing Alpha-1 MZ Individuals Shows Frequent Biallelic Mutations

RATIONALE: Individuals with a single Z mutation in the SERPINA1 gene that codes for alpha-1 antitrypsin (AAT) are at increased risk for COPD if they have ever-smoked. Whether additional variants alter the risk for COPD in this population remains unknown. OBJECTIVES: To determine whether additional S...

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Autores principales: Foil, Kimberly E., Blanton, M. Gwen, Sanders, Chris, Kim, Joannah, Al Ashry, Haitham S., Kumbhare, Suchit, Strange, Charlie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145046/
https://www.ncbi.nlm.nih.gov/pubmed/30254761
http://dx.doi.org/10.1155/2018/2836389
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author Foil, Kimberly E.
Blanton, M. Gwen
Sanders, Chris
Kim, Joannah
Al Ashry, Haitham S.
Kumbhare, Suchit
Strange, Charlie
author_facet Foil, Kimberly E.
Blanton, M. Gwen
Sanders, Chris
Kim, Joannah
Al Ashry, Haitham S.
Kumbhare, Suchit
Strange, Charlie
author_sort Foil, Kimberly E.
collection PubMed
description RATIONALE: Individuals with a single Z mutation in the SERPINA1 gene that codes for alpha-1 antitrypsin (AAT) are at increased risk for COPD if they have ever-smoked. Whether additional variants alter the risk for COPD in this population remains unknown. OBJECTIVES: To determine whether additional SERPINA1 variants impact COPD development in a previously identified MZ (carrier) cohort. METHODS: Individuals with prior MZ results and AAT serum level <16uM were recruited from the Alpha-1 Coded Testing study and Alpha-1 Foundation Research Registry. Participants completed smoking history, demographics, and COPD Severity Score (Range 0-33) using REDCap data capture. At-home finger-stick tests were performed for next generation sequencing (NGS) at the Biocerna LLC laboratory. A genetic counselor reviewed records and interviewed participants with additional variants by NGS. A Wilcoxon Rank Sum test was used to assess correlation between variants and the COPD severity score. RESULTS: A second SERPINA1 variant of known or possible significance was identified in 6 (5.8%) participants. One each of ZZ, SZ, FZ, ZSmunich, ZM2obernburg, and Z/c.922G>T genotypes were identified. ZZ, SZ, and FZ are known pathogenic genotypes. Smunich is a likely pathogenic variant. M2obernburg and c.922G>T are variants of uncertain significance. The ZZ individual was on augmentation therapy when determined MZ by protease inhibitor (Pi) phenotyping; the others had limited targeted genotyping with MZ results. These six participants with biallelic variants had positive COPD severity scores >1. Presence of additional variants was not significantly associated with COPD symptoms in this small sample size. CONCLUSIONS: Some diagnosed MZ individuals instead have biallelic variants. Larger studies are needed to determine COPD-risk liability of variants. Accurate diagnosis impacts medical management and familial risk assessment. Pi phenotyping can be confounded by augmentation therapy and liver transplantation. Because a normal M allele may be reported in the absence of tested mutation(s) in AATD genotyping, clinicians should consider clinical circumstances and laboratory methods when selecting and interpreting AATD tests. Advanced testing, including NGS, may be beneficial for select individuals with prior MZ results. CLINICAL TRIAL REGISTRATION: This study was registered with clinicaltrials.gov (NCT NCT02810327).
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spelling pubmed-61450462018-09-25 Sequencing Alpha-1 MZ Individuals Shows Frequent Biallelic Mutations Foil, Kimberly E. Blanton, M. Gwen Sanders, Chris Kim, Joannah Al Ashry, Haitham S. Kumbhare, Suchit Strange, Charlie Pulm Med Research Article RATIONALE: Individuals with a single Z mutation in the SERPINA1 gene that codes for alpha-1 antitrypsin (AAT) are at increased risk for COPD if they have ever-smoked. Whether additional variants alter the risk for COPD in this population remains unknown. OBJECTIVES: To determine whether additional SERPINA1 variants impact COPD development in a previously identified MZ (carrier) cohort. METHODS: Individuals with prior MZ results and AAT serum level <16uM were recruited from the Alpha-1 Coded Testing study and Alpha-1 Foundation Research Registry. Participants completed smoking history, demographics, and COPD Severity Score (Range 0-33) using REDCap data capture. At-home finger-stick tests were performed for next generation sequencing (NGS) at the Biocerna LLC laboratory. A genetic counselor reviewed records and interviewed participants with additional variants by NGS. A Wilcoxon Rank Sum test was used to assess correlation between variants and the COPD severity score. RESULTS: A second SERPINA1 variant of known or possible significance was identified in 6 (5.8%) participants. One each of ZZ, SZ, FZ, ZSmunich, ZM2obernburg, and Z/c.922G>T genotypes were identified. ZZ, SZ, and FZ are known pathogenic genotypes. Smunich is a likely pathogenic variant. M2obernburg and c.922G>T are variants of uncertain significance. The ZZ individual was on augmentation therapy when determined MZ by protease inhibitor (Pi) phenotyping; the others had limited targeted genotyping with MZ results. These six participants with biallelic variants had positive COPD severity scores >1. Presence of additional variants was not significantly associated with COPD symptoms in this small sample size. CONCLUSIONS: Some diagnosed MZ individuals instead have biallelic variants. Larger studies are needed to determine COPD-risk liability of variants. Accurate diagnosis impacts medical management and familial risk assessment. Pi phenotyping can be confounded by augmentation therapy and liver transplantation. Because a normal M allele may be reported in the absence of tested mutation(s) in AATD genotyping, clinicians should consider clinical circumstances and laboratory methods when selecting and interpreting AATD tests. Advanced testing, including NGS, may be beneficial for select individuals with prior MZ results. CLINICAL TRIAL REGISTRATION: This study was registered with clinicaltrials.gov (NCT NCT02810327). Hindawi 2018-09-05 /pmc/articles/PMC6145046/ /pubmed/30254761 http://dx.doi.org/10.1155/2018/2836389 Text en Copyright © 2018 Kimberly E. Foil et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Foil, Kimberly E.
Blanton, M. Gwen
Sanders, Chris
Kim, Joannah
Al Ashry, Haitham S.
Kumbhare, Suchit
Strange, Charlie
Sequencing Alpha-1 MZ Individuals Shows Frequent Biallelic Mutations
title Sequencing Alpha-1 MZ Individuals Shows Frequent Biallelic Mutations
title_full Sequencing Alpha-1 MZ Individuals Shows Frequent Biallelic Mutations
title_fullStr Sequencing Alpha-1 MZ Individuals Shows Frequent Biallelic Mutations
title_full_unstemmed Sequencing Alpha-1 MZ Individuals Shows Frequent Biallelic Mutations
title_short Sequencing Alpha-1 MZ Individuals Shows Frequent Biallelic Mutations
title_sort sequencing alpha-1 mz individuals shows frequent biallelic mutations
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145046/
https://www.ncbi.nlm.nih.gov/pubmed/30254761
http://dx.doi.org/10.1155/2018/2836389
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