PubMed · 41001506
Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways.
Abstract
Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. FGF21, RPTOR, and IFNL3/4). Fifteen cirrhosis loci exhibited differential effects on cirrhosis risk via underlying etiologies, and six HCC loci influenced HCC risk indirectly via cirrhosis. In a gene-burden analysis of rare variants from whole-genome sequencing data in the VA Million Veteran Program (n=102,677), we identified GSTA5 as a novel cirrhosis-associated gene, while APOB and ATP9B were associated with and replicated for HCC. A high genetic risk score for cirrhosis was associated with a nearly doubled risk of CLD progressing to cirrhosis (HR=1.94, P=2×10-68) and of cirrhosis progressing to HCC (HR=1.65, P=7×10-08). Finally, among individuals with chronic hepatitis C who underwent antiviral therapy, cirrhosis risk was modified by variants in PNPLA3, IFNL3/4, and CD81 following pegylated interferon-α therapy, and by APOE lead variant following direct-acting antiviral therapy. These findings provide new insights into the complex genetic architecture of CLD progression with potential clinical and therapeutic implications.
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Marijana Vujkovic, David E Kaplan, Jonas Ghouse, Bao-Li Loza, Joseph Brancale, Adam Lewis, David Y Zhang, Michael G Levin, Olivia J Veatch, Josephine P Johnson, Carolin V Schneider, Anurag Verma, Kirk J Wangensteen, Eleonora Scorletti, Dipender Gill, Chigoziri Konkwo, Alexis M Garófalo, Lindsay A Guare, Tae-Wi Schwantes-An, Marco V Abreu, Helene Gellert-Kristensen, Ole B Pedersen, Christian Erikstrup, Johan S Bundgaard, Erik Sørensen, Sisse R Ostrowski, Henning Bundgaard, Kyung Min Lee, Abraham Shaked, Kim M Olthoff, Maarouf A Hoteit, Elizabeth K Speliotes, Yanhua Chen, Antonino Oliveri, Lishi Yin, Luca Vc Valenti, Francesco Malvestiti, Daniele Marchelli, Lorenzo Miano, Quentin M Anstee, Ann K Daly, Heather J Cordell, Rebecca Darlay, Niek Verweij, George Hindy, Adam Locke, Kentaro Matsuura, Sumeet K Asrani, Giuliano Testa, Luca A Lotta, Marcus B Jones, Daniel R Dochtermann, Trina M Norden-Krichmar, Craig C Teerlink, Poornima Devineni, Saiju Pyarajan, Daniel J Rader, Yasuhito Tanaka, Benjamin F Voight, Silvia Vilarinho, Lisa A Bastarache, Stefan Stender, Philip S Tsao, Penn Medicine Biobank, DBDS Genomic Consortium, BioVU Biobank, Michigan Genomics Initiative, Regeneron Genetics Center, Indiana Biobank, All Of Us Research Program, Milano Biobank, LITMUS Consortium, VA Million Veteran Program, Timothy R Morgan, Julie A Lynch, Kyong-Mi Chang. 2025-09-18. Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways.. https://doi.org/10.1101/2025.09.16.25335186
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