Heterozygosity of the Alpha 1‐Antitrypsin Pi*Z Allele and Risk of Liver Disease
Year: 2021
Type: article
Study design: Observational Study
Abstract: The serpin family A member 1 (SERPINA1) Z allele is present in approximately one in 25 individuals of European ancestry. Z allele homozygosity (Pi*ZZ) is the most common cause of alpha 1‐antitrypsin deficiency and is a proven risk factor for cirrhosis. We examined whether heterozygous Z allele (Pi*Z) carriers in United Kingdom (UK) Biobank, a population‐based cohort, are at increased risk of liver disease. We replicated findings in Massachusetts General Brigham Biobank, a hospital‐based cohort. We also examined variants associated with liver disease and assessed for gene–gene and gene–environment interactions. In UK Biobank, we identified 1,493 cases of cirrhosis, 12,603 Z allele heterozygotes, and 129 Z allele homozygotes among 312,671 unrelated white British participants. Heterozygous carriage of the Z allele was associated with cirrhosis compared to noncarriage (odds ratio [OR], 1.53; P = 1.1×10−04); homozygosity of the Z allele also increased the risk of cirrhosis (OR, 11.8; P = 1.8 × 10−09). The OR for cirrhosis of the Z allele was comparable to that of well‐established genetic variants, including patatin‐like phospholipase domain containing 3 (PNPLA3) I148M (OR, 1.48; P = 1.1 × 10−22) and transmembrane 6 superfamily member 2 (TM6SF2) E167K (OR, 1.34; P = 2.6 × 10−06). In heterozygotes compared to noncarriers, the Z allele was associated with higher alanine aminotransferase (ALT; P = = 4.6 × 10−46), aspartate aminotransferase (AST; P = 2.2 × 10−27), alkaline phosphatase (P = 3.3 × 10−43), gamma‐glutamyltransferase (P = 1.2 × 10−05), and total bilirubin (P = 6.4 × 10−06); Z allele homozygotes had even greater elevations in liver biochemistries. Body mass index (BMI) amplified the association of the Z allele for ALT (P interaction = 0.021) and AST (P interaction = 0.0040), suggesting a gene–environment interaction. Finally, we demonstrated genetic interactions between variants in PNPLA3, TM6SF2, and hydroxysteroid 17‐beta dehydrogenase 13 (HSD17B13); there was no evidence of epistasis between the Z allele and these variants. Conclusion: SERPINA1 Z allele heterozygosity is an important risk factor for liver disease; this risk is amplified by increasing BMI.
Source: Hepatology Communications
DOI: 10.1002/hep4.1718
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: Adenosine deaminase 2 regulates macrophage phenotype and liver fibrosis in nonalcoholic fatty liver disease, Mechanistic insights into asthma pathogenesis through the integration of asthma genes, risk exposures, and metabolomics, Deciphering the Genetic Basis of Portal Hypertension, Integrative Metabolomics of Asthma Severity, Identifying functional variants in COPD GWAS loci, Network-based Methods for Understanding Genetic Determinants and Epistasis in COPD, Genetic and Functional Dissection of a Cluster of COPD GWAS Signals on Chromosome 4q, (2 of 2) Genetic Epidemiology of COPD, (2 of 2) Genetic Epidemiology of COPD, G5850737185, Multi-omic Subtyping of Chronic Obstructive Pulmonary Disease, COPD Susceptibility, Heterogeneity, and Progression: Proteomics and Genetics, Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers, SYSTEMS APPROACHES TO THE EPIDEMIOLOGY, GENETICS AND GENOMICS OF LUNG DISEASES, Genetic and Genomic Characterization of the Occurrence and Progression of Interstitial Lung Abnormalities
OpenAlex ID: W3141752809