Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways
Vujkovic, M.; Kaplan, D. E.; Ghouse, J.; Loza, B.-L.; Brancale, J.; Lewis, A.; Zhang, D. Y.; Levin, M. G.; Veatch, O. J.; Johnson, J. P.; Schneider, C. V.; Verma, A.; Wangensteen, K. J.; Scorletti, E.; Gill, D.; Konkwo, C.; Garofalo, A. M.; Guare, L. A.; Schwantes-An, T.-W.; Abreu, M. V.; Gellert-Kristensen, H.; Pedersen, O. B.; Erikstrup, C.; Bundgaard, J. S.; Sorensen, E.; Ostrowski, S. R.; Bundgaard, H.; Lee, K. M.; Shaked, A.; Olthoff, K. M.; Hoteit, M. A.; Speliotes, E. K.; Chen, Y.; Oliveri, A.; Yin, L.; Valenti, L. V.; Malvestiti, F.; Marchelli, D.; Miano, L.; Anstee, Q. M.; Daly, A. K.
Show 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=2x10-68) and of cirrhosis progressing to HCC (HR=1.65, P=7x10-08). 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- 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.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Liver Sinusoidal Endothelial Cells and Laminin dictate cholangiocytes fate in chronic liver disease 93%
- Mendelian Randomization Analysis Dissects the Relationship between NAFLD, T2D, and Obesity and Provides Implications to Precision Medicine 92%
- Integrative molecular profiling of autoreactive CD4 T cells in autoimmune hepatitis 92%
Similar papers in this journal
Similar papers in this journal
Similar papers in this journal
- A single-cell fixed RNA profiling of liver fibrosis progression and regression reveals SEMA4D and LMCD1 as key mediators of fibrogenesis 94%
- Classification of virologic trajectories during nucleos/tide analogue treatment of hepatitis B virus (HBV) infection 92%
- Identification and functional characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease 92%
Similar papers in this journal
- Single Nucleus RNA Sequencing of Pre-Malignant Liver Reveals Disease-Associated Hepatocyte State with HCC Prognostic Potential 95%
- Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of multiple cardiovascular disease risk factors 93%
- Temporal multi-omic analysis of COVID-19 in end-stage kidney disease 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.