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Alpha-1 antitrypsin deficiency liver disease, mutational homogeneity modulated by epigenetic heterogeneity with links to obesity.

Alpha-1 Antitrypsin Deficiency (AATD) liver disease is characterized by marked heterogeneity in presentation and progression despite a common underlying gene mutation, strongly suggesting the involvement of other genetic and/or epigenetic modifiers. Variation in clinical phenotype has added to the challenge of detection, diagnosis, and testing of new therapies in AATD patients. We examined the contribution of DNA methylation (5mC) to AATD liver disease heterogeneity since 5mC responds to environmental and genetic cues, and its deregulation is a major driver of liver disease. Using liver biopsies from early-stage AATD adults with ZZ genotype, genome-wide 5mC patterns were interrogated. We compared DNA methylation among early AATD patients, and with normal, cirrhotic, and HCC liver derived from multiple etiologic exposures, and linked patient clinical/demographic features. Global analysis revealed significant genomic hypomethylation in AATD liver impacting genes related to liver cancer, cell cycle, and fibrosis, as well as key regulatory molecules influencing growth, migration, and immune function. Further analysis indicates 5mC changes are localized, with hypermethylation occurring within a background of genome-wide 5mC loss, and AATD patients manifesting distinct epigenetic landscapes despite their mutational homogeneity. By integrating clinical data with 5mC landscapes, we observe that CpGs differentially methylated among AATD disease patients are linked to hallmark clinical features of AATD (e.g. hepatocyte degeneration and polymer accumulation) and further reveal links to well-known gender-specific effects of liver disease progression Conclusion Our data reveal novel molecular epigenetic signatures within this mutationally homogeneous group that point to new ways to stratify patients for liver disease risk. This article is protected by copyright. All rights reserved.

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