Objective: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. - Design: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case–control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). - Results: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10⁻⁹, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10⁻⁵, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10⁻⁴⁴). - Conclusion: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:89012 |
| Date | 22 February 2024 |
| Creators | Buch, Stephan, Innes, Hamish, Lutz, Philipp Ludwig, Nischalke, Hans Dieter, Marquardt, Jens U., Fischer, Janett, Weiss, Karl Heinz, Rosendahl, Jonas, Marot, Astrid, Krawczyk, Marcin, Casper, Markus, Lammert, Frank, Eyer, Florian, Vogel, Arndt, Marhenke, Silke, von Felden, Johann, Sharma, Rohini, Atkinson, Stephen Rahul, McQuillin, Andrew, Nattermann, Jacob, Schafmayer, Clemens, Franke, Andre, Strassburg, Christian, Rietschel, Marcella, Altmann, Heidi, Sulk, Stefan, Thangapandi, Veera Raghavan, Brosch, Mario, Lackner, Carolin, Stauber, Rudolf E, Canbay, Ali, Link, Alexander, Reiberger, Thomas, Mandorfer, Matthias, Semmler, Georg, Scheiner, Bernhard, Datz, Christian, Romeo, Stefano, Corradini, Stefano Ginanni, Irving, William Lucien, Morling, Joanne R, Guha, Indra Neil, Barnes, Eleanor, Ansari, M Azim, Quistrebert, Jocelyn, Valenti, Luca, Müller, Sascha A, Morgan, Marsha Yvonne, Dufour, Jean-François, Trebicka, Jonel, Berg, Thomas, Deltenre, Pierre, Mueller, Sebastian, Hampe, Jochen, Stickel, Felix |
| Publisher | BMJ Publishing Group |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 1468-3288, 10.1136/gutjnl-2022-327196, info:eu-repo/grantAgreement/Bundesministerium für Bildung und Forschung/Detaillierte Analyse der räumlichen Organisation der Entstehung des hepatozellulären Karzinoms (DEEP-HCC)/031L0258A//Systemmedizinisches Forschungsnetz zur Früherkennung und Prävention von Leberkrebs/LiSyM-Krebs, info:eu-repo/grantAgreement/Deutsche Forschungsgemeinschaft/SFB 1382: Die Darm-Leber Achse – Funktionelle Zusammenhänge und therapeutische Strategien/403224013//Die Rolle des Darmmikrobioms bei der Dekompensation chronischer Lebererkrankungen mit Pfortaderhochdruck/(A09), info:eu-repo/grantAgreement/UK Research and Innovation/MRC/MC_UU_12014/1//Viral Hepatitis, info:eu-repo/grantAgreement/UK Research and Innovation/MRC/MR/K01532X/1//Stratified Medicine to Optimise Treatment for Hepatitis C Virus Infection, info:eu-repo/grantAgreement/European Commission/H2020 | RIA/825694//MICROBiome-based biomarkers to PREDICT decompensation of liver cirrhosis and treatment response/MICROB-PREDICT, info:eu-repo/grantAgreement/European Commission/H2020 | RIA/847949//Decompensated cirrhosis: Identification of new combinatorial therapies based on systems approaches/DECISION, info:eu-repo/grantAgreement/European Commission/H2020 | RIA/668031//GALAXY: Gut-and-liver axis in alcoholic liver fibrosis/GALAXY, info:eu-repo/grantAgreement/European Commission/H2020 | RIA/731875//Simvastatin and rifaximin as new therapy for patients with decompensated cirrhosis/LIVERHOPE, info:eu-repo/grantAgreement/European Commission/H2020 | CSA/964590//International Human Microbiome Coordination and Support Action/IHMCSA |
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