Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways
| Title: | Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways |
|---|---|
| Authors: | Vujkovic M; Kaplan DE; Ghouse J; Loza BL; Brancale J; Lewis A; Zhang DY; Levin MG; Veatch OJ; Johnson JP; Schneider CV; Verma A; Wangensteen KJ; Scorletti E; Gill D; Konkwo C; Garófalo AM; Guare LA; Schwantes-An TW; Abreu MV; Gellert-Kristensen H; Pedersen OB; Erikstrup C; Bundgaard JS; Sørensen E; Ostrowski SR; Bundgaard H; Lee KM; Shaked A; Olthoff KM; Hoteit MA; Speliotes EK; Chen Y; Oliveri A; Yin L; Valenti L; Malvestiti F; Marchelli D; Miano L; Anstee QM; Daly AK; Cordell HJ; Darlay R; Verweij N; Hindy G; Locke A; Matsuura K; Asrani SK; Testa G; Lotta LA; Jones MB; Dochtermann DR; Norden-Krichmar TM; Teerlink CC; Devineni P; Pyarajan S; Rader DJ; Tanaka Y; Voight BF; Vilarinho S; Bastarache LA; Stender S; Tsao PS; 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; Morgan TR; Lynch JA; Chang KM |
| Contributors: | M. Vujkovic; D. Kaplan; J. Ghouse; B. Loza; J. Brancale; A. Lewi; D. Zhang; M. Levin; O. Veatch; J. Johnson; C. Schneider; A. Verma; K. Wangensteen; E. Scorletti; D. Gill; C. Konkwo; A. Garófalo; L. Guare; T. Schwantes-An; M. Abreu; H. Gellert-Kristensen; O. Pedersen; C. Erikstrup; J. Bundgaard; E. Sørensen; S. Ostrowski; H. Bundgaard; K. Lee; A. Shaked; K. Olthoff; M. Hoteit; E. Speliote; Y. Chen; A. Oliveri; L. Yin; L. Valenti; F. Malvestiti; D. Marchelli; L. Miano; Q. Anstee; A. Daly; H. Cordell; R. Darlay; N. Verweij; G. Hindy; A. Locke; K. Matsuura; S. Asrani; G. Testa; L. Lotta; M. Jone; D. Dochtermann; T. Norden-Krichmar; C. Teerlink; P. Devineni; S. Pyarajan; D. Rader; Y. Tanaka; B. Voight; S. Vilarinho; L. Bastarache; S. Stender; P. Tsao; B. Penn Medicine; C. Dbds Genomic; B. Biovu; I. Michigan Genomic; C. Regeneron Genetic; B. Indiana; P. All Of Us Research; B. Milano; C. Litmu; P. Va Million Veteran; T. Morgan; J. Lynch; K. Chang |
| Publication Year: | 2025 |
| Collection: | The University of Milan: Archivio Istituzionale della Ricerca (AIR) |
| Subject Terms: | Settore MEDS-05/A - Medicina interna |
| Description: | 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. |
| Document Type: | article in journal/newspaper |
| Language: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/41001506; numberofpages:59; https://hdl.handle.net/2434/1226395 |
| DOI: | 10.1101/2025.09.16.25335186 |
| DOI: | 10.1101/2025.09.16.25335186v1.article-info |
| Availability: | https://hdl.handle.net/2434/1226395; https://doi.org/10.1101/2025.09.16.25335186; https://www.medrxiv.org/content/10.1101/2025.09.16.25335186v1.article-info |
| Rights: | info:eu-repo/semantics/openAccess ; license:Creative commons ; license uri:http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: | edsbas.BA87070F |
| Database: | BASE |