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

• Published in: PloS one Vol. 18; no. 8; p. e0286469
• Main Authors: Schuler, Bryce A., Bastarache, Lisa, Wang, Janey, He, Jing, Van Driest, Sara L., Denny, Joshua C.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31.08.2023; Public Library of Science (PLoS)
• Subjects: 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
• DOI: 10.1371/journal.pone.0286469

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.