Population genetic testing and SERPINA1 sequencing identifies unidentified alpha-1 antitrypsin deficiency alleles and gene-environment interaction with hepatitis C infection.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2023
2023
Historique:
received:
19
01
2023
accepted:
16
05
2023
medline:
4
9
2023
pubmed:
31
8
2023
entrez:
31
8
2023
Statut:
epublish
Résumé
Alpha-1 antitrypsin deficiency (AATD), a relatively common autosomal recessive genetic disorder, is underdiagnosed in symptomatic individuals. We sought to compare the risk of liver transplantation associated with hepatitis C infection with AATD heterozygotes and homozygotes and determine if SERPINA1 sequencing would identify undiagnosed AATD. We performed a retrospective cohort study in a deidentified Electronic Health Record (EHR)-linked DNA biobank with 72,027 individuals genotyped for the M, Z, and S alleles in SERPINA1. We investigated liver transplantation frequency by genotype group and compared with hepatitis C infection. We performed SERPINA1 sequencing in carriers of pathogenic AATD alleles who underwent liver transplantation. Liver transplantation was associated with the Z allele (ZZ: odds ratio [OR] = 1.31, p<2e-16; MZ: OR = 1.02, p = 1.2e-13) and with hepatitis C (OR = 1.20, p<2e-16). For liver transplantation, there was a significant interaction between genotype and hepatitis C (ZZ: interaction OR = 1.23, p = 4.7e-4; MZ: interaction OR = 1.11, p = 6.9e-13). Sequencing uncovered a second, rare, pathogenic SERPINA1 variant in six of 133 individuals with liver transplants and without hepatitis C. Liver transplantation was more common in individuals with AATD risk alleles (including heterozygotes), and AATD and hepatitis C demonstrated evidence of a gene-environment interaction in relation to liver transplantation. The current AATD screening strategy may miss diagnoses whereas SERPINA1 sequencing may increase diagnostic yield for AATD, stratify risk for liver disease, and inform clinical management for individuals with AATD risk alleles and liver disease risk factors.
Identifiants
pubmed: 37651384
doi: 10.1371/journal.pone.0286469
pii: PONE-D-23-01752
pmc: PMC10470904
doi:
Substances chimiques
SERPINA1 protein, human
0
alpha 1-Antitrypsin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0286469Subventions
Organisme : NLM NIH HHS
ID : R01 LM010685
Pays : United States
Organisme : NHLBI NIH HHS
ID : R38 HL143619
Pays : United States
Informations de copyright
Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Nat Biotechnol. 2013 Dec;31(12):1102-10
pubmed: 24270849
Clin Chem Lab Med. 2021 Mar 05;59(8):1384-1391
pubmed: 33675199
Chronic Obstr Pulm Dis. 2016 Jun 6;3(3):668-682
pubmed: 28848891
Gene. 2011 Dec 10;489(2):98-102
pubmed: 21925577
Respir Med. 2009 Mar;103(3):335-41
pubmed: 19013782
J Hepatol. 2011 Apr;54(4):795-809
pubmed: 21145844
N Engl J Med. 2022 Aug 11;387(6):514-524
pubmed: 35748699
Liver Transpl. 2018 Jun;24(6):744-751
pubmed: 29573137
J Clin Med. 2022 Dec 29;12(1):
pubmed: 36615054
Am J Hum Genet. 1990 Mar;46(3):602-12
pubmed: 2309708
World J Hepatol. 2014 Feb 27;6(2):92-7
pubmed: 24575168
Thorax. 2004 Mar;59(3):259-64
pubmed: 14985567
Pulm Med. 2018 Sep 05;2018:2836389
pubmed: 30254761
Ther Adv Respir Dis. 2012 Oct;6(5):277-95
pubmed: 22933512
Clin Liver Dis. 2004 Nov;8(4):839-59, viii-ix
pubmed: 15464658
Hepatology. 1997 Sep;26(3):776-9
pubmed: 9303512
COPD. 2013 Mar;10 Suppl 1:35-43
pubmed: 23527737
Am J Respir Crit Care Med. 2003 Oct 1;168(7):818-900
pubmed: 14522813
Science. 2018 Mar 16;359(6381):1233-1239
pubmed: 29590070
Eur J Hum Genet. 2011 May;19(5):
pubmed: 21248733
J Am Med Inform Assoc. 2019 Dec 1;26(12):1437-1447
pubmed: 31609419
Per Med. 2013 Sep;10(7):
pubmed: 24363766
Lancet Respir Med. 2019 Dec;7(12):1059-1067
pubmed: 31324540
N Engl J Med. 2020 Apr 9;382(15):1443-1455
pubmed: 32268028
J Intern Med. 2014 Oct;276(4):311-35
pubmed: 24661570
Am Rev Respir Dis. 1989 Oct;140(4):961-6
pubmed: 2679271
COPD. 2013 Mar;10 Suppl 1:26-34
pubmed: 23527684
Am J Physiol Gastrointest Liver Physiol. 2004 May;286(5):G851-62
pubmed: 14684378
Gastroenterology. 2020 Aug;159(2):534-548.e11
pubmed: 32376409
Curr Gastroenterol Rep. 2006 Feb;8(1):14-20
pubmed: 16510030
J Hepatol. 2022 Apr;76(4):946-958
pubmed: 34848258
Chest. 2005 May;127(5):1537-43
pubmed: 15888825
Respir Med. 2000 Aug;94 Suppl C:S12-5
pubmed: 10954249
Hum Genet. 1989 Feb;81(3):264-8
pubmed: 2784123
Ann Intern Med. 1992 Oct 15;117(8):641-5
pubmed: 1530195
JMIR Med Inform. 2019 Nov 29;7(4):e14325
pubmed: 31553307
J Pediatr Gastroenterol Nutr. 2006 Jul;43 Suppl 1:S30-5
pubmed: 16819398
Bull World Health Organ. 1997;75(5):397-415
pubmed: 9447774
Int J Chron Obstruct Pulmon Dis. 2019 Nov 18;14:2535-2542
pubmed: 31819391
Clin Respir J. 2017 Jan;11(1):90-97
pubmed: 25919395
Clin Pharmacol Ther. 2008 Sep;84(3):362-9
pubmed: 18500243
Am J Respir Cell Mol Biol. 2008 Jan;38(1):114-20
pubmed: 17690329
J Gastrointestin Liver Dis. 2006 Jun;15(2):131-5
pubmed: 16802007
PLoS One. 2017 Jul 7;12(7):e0175508
pubmed: 28686612
BMC Pulm Med. 2014 Aug 07;14:132
pubmed: 25098359
Respir Med. 2016 Jul;116:8-18
pubmed: 27296815
Liver Transpl. 2013 Dec;19(12):1370-6
pubmed: 24019185
Genome Res. 2009 Sep;19(9):1655-64
pubmed: 19648217
Gastroenterology. 2021 Apr;160(5):1874-1875
pubmed: 33385428
Am J Gastroenterol. 1997 Apr;92(4):602-7
pubmed: 9128307