PMID- 37651384
OWN - NLM
STAT- MEDLINE
DCOM- 20230904
LR  - 20240103
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 18
IP  - 8
DP  - 2023
TI  - Population genetic testing and SERPINA1 sequencing identifies unidentified 
      alpha-1 antitrypsin deficiency alleles and gene-environment interaction with 
      hepatitis C infection.
PG  - e0286469
LID - 10.1371/journal.pone.0286469 [doi]
LID - e0286469
AB  - 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.
CI  - 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.
FAU - Schuler, Bryce A
AU  - Schuler BA
AUID- ORCID: 0000-0001-9111-3702
AD  - Department of Pediatrics, Vanderbilt University Medical Center, Nashville, 
      Tennessee, United States of America.
AD  - Department of Biomedical Informatics, Vanderbilt University Medical Center, 
      Nashville, Tennessee, United States of America.
FAU - Bastarache, Lisa
AU  - Bastarache L
AD  - Department of Biomedical Informatics, Vanderbilt University Medical Center, 
      Nashville, Tennessee, United States of America.
FAU - Wang, Janey
AU  - Wang J
AD  - Department of Biostatistics, Vanderbilt University Medical Center, Nashville, 
      Tennessee, United States of America.
FAU - He, Jing
AU  - He J
AD  - Department of Biomedical Informatics, Vanderbilt University Medical Center, 
      Nashville, Tennessee, United States of America.
FAU - Van Driest, Sara L
AU  - Van Driest SL
AD  - Department of Pediatrics, Vanderbilt University Medical Center, Nashville, 
      Tennessee, United States of America.
AD  - Department of Medicine, Vanderbilt University Medical Center, Nashville, 
      Tennessee, United States of America.
FAU - Denny, Joshua C
AU  - Denny JC
AD  - All of Us Research Program, National Institutes of Health, Bethesda, Maryland, 
      United States of America.
AD  - National Human Genome Research Institute, National Institutes of Health, 
      Bethesda, Maryland, United States of America.
LA  - eng
GR  - K12 HD087023/HD/NICHD NIH HHS/United States
GR  - R01 LM010685/LM/NLM NIH HHS/United States
GR  - R38 HL143619/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230831
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (SERPINA1 protein, human)
RN  - 0 (alpha 1-Antitrypsin)
SB  - IM
MH  - Humans
MH  - Alleles
MH  - Gene-Environment Interaction
MH  - Retrospective Studies
MH  - *alpha 1-Antitrypsin Deficiency/diagnosis/genetics
MH  - *Hepatitis C/genetics
MH  - Hepacivirus/genetics
MH  - Genetics, Population
MH  - alpha 1-Antitrypsin/genetics
PMC - PMC10470904
COIS- The authors have declared that no competing interests exist.
EDAT- 2023/08/31 18:41
MHDA- 2023/09/04 06:42
PMCR- 2023/08/31
CRDT- 2023/08/31 13:35
PHST- 2023/01/19 00:00 [received]
PHST- 2023/05/16 00:00 [accepted]
PHST- 2023/09/04 06:42 [medline]
PHST- 2023/08/31 18:41 [pubmed]
PHST- 2023/08/31 13:35 [entrez]
PHST- 2023/08/31 00:00 [pmc-release]
AID - PONE-D-23-01752 [pii]
AID - 10.1371/journal.pone.0286469 [doi]
PST - epublish
SO  - PLoS One. 2023 Aug 31;18(8):e0286469. doi: 10.1371/journal.pone.0286469. 
      eCollection 2023.