Population genetic testing and SERPINA1 sequencing identifies unidentified alpha-1 antitrypsin deficiency alleles and gene-environment interaction with hepatitis C infection

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 SERPINA...

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Veröffentlicht in:PloS one Jg. 18; H. 8; S. e0286469
Hauptverfasser: Schuler, Bryce A., Bastarache, Lisa, Wang, Janey, He, Jing, Van Driest, Sara L., Denny, Joshua C.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Public Library of Science 31.08.2023
Public Library of Science (PLoS)
Schlagworte:
Alcohol
Alleles
alpha 1-Antitrypsin - genetics
Alpha 1-antitrypsin deficiency
alpha 1-Antitrypsin Deficiency - diagnosis
alpha 1-Antitrypsin Deficiency - genetics
Biobanks
Biology and Life Sciences
Care and treatment
Chronic obstructive pulmonary disease
Codes
Counties
Deoxyribonucleic acid
Diagnosis
DNA
Electronic health records
Electronic medical records
Evaluation
Gene-Environment Interaction
Genealogy
Genetic disorders
Genetic screening
Genetic testing
Genetics, Population
Genotype & phenotype
Genotype-environment interactions
Genotypes
Health risk assessment
Health risks
Hepacivirus - genetics
Hepatitis
Hepatitis C
Hepatitis C - genetics
Hepatitis C virus
Hereditary diseases
Heterozygotes
Homozygotes
Human subjects
Humans
Infections
Liver
Liver diseases
Liver transplantation
Liver transplants
Medicine and health sciences
Population genetics
Retrospective Studies
Risk factors
Transplantation
Transplants
United States
ISSN:1932-6203, 1932-6203
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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Competing Interests: The authors have declared that no competing interests exist.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0286469