Genetic variation inTERTmodifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study
Author:
Buch StephanORCID, Innes HamishORCID, Lutz Philipp Ludwig, Nischalke Hans Dieter, Marquardt Jens U, Fischer Janett, Weiss Karl Heinz, Rosendahl JonasORCID, Marot Astrid, Krawczyk Marcin, Casper Markus, Lammert Frank, Eyer Florian, Vogel Arndt, Marhenke Silke, von Felden JohannORCID, Sharma RohiniORCID, Atkinson Stephen Rahul, McQuillin Andrew, Nattermann JacobORCID, Schafmayer Clemens, Franke AndreORCID, Strassburg ChristianORCID, Rietschel Marcella, Altmann Heidi, Sulk Stefan, Thangapandi Veera Raghavan, Brosch Mario, Lackner Carolin, Stauber Rudolf E, Canbay AliORCID, Link Alexander, Reiberger ThomasORCID, Mandorfer MattiasORCID, Semmler Georg, Scheiner BernhardORCID, Datz ChristianORCID, Romeo StefanoORCID, Ginanni Corradini Stefano, Irving William LucienORCID, Morling Joanne R, Guha Indra NeilORCID, Barnes Eleanor, Ansari M Azim, Quistrebert Jocelyn, Valenti LucaORCID, Müller Sascha A, Morgan Marsha Yvonne, Dufour Jean-François, Trebicka JonelORCID, Berg ThomasORCID, Deltenre Pierre, Mueller Sebastian, Hampe JochenORCID, Stickel Felix
Abstract
ObjectiveHepatocellular 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.DesignPatients 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).ResultsAssociations with variants rs738409 inPNPLA3and rs58542926 inTM6SF2previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) inTERT(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) inTERTwas associated with an increased leucocyte telomere length (p=2.12×10−44).ConclusionThis study identifies rs2242652 inTERTas a novel protective factor for HCC in patients with alcohol-related cirrhosis.
Funder
Deliver study IHMCSA GALAXY LIVERHOPE UK Medical Research Council, United Kingdom Medical Research Foundation Swiss Foundation for Alcohol Research German Federal Ministry for Education and Research DECISION Deutsche Krebshilfe MICROB-PREDICT European Union’s Horizon 2020 Swiss National Funds LiSyMKrebs (DEEP-HCC) network Ministry of Economy, Science and Digitalization of Saxony-Anhalt European funds for regional development” German Research Foundation
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26 articles.
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