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Genetic variation in <i>TERT</i> modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study.

ABSTRACT:

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.

SUBMITTER: Buch S 

PROVIDER: S-EPMC9872243 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Genetic variation in &lt;i&gt;TERT&lt;/i&gt; modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study.

Buch Stephan S   Innes Hamish H   Lutz Philipp Ludwig PL   Nischalke Hans Dieter HD   Marquardt Jens U JU   Fischer Janett J   Weiss Karl Heinz KH   Rosendahl Jonas J   Marot Astrid A   Krawczyk Marcin M   Casper Markus M   Lammert Frank F   Eyer Florian F   Vogel Arndt A   Marhenke Silke S   von Felden Johann J   Sharma Rohini R   Atkinson Stephen Rahul SR   McQuillin Andrew A   Nattermann Jacob J   Schafmayer Clemens C   Franke Andre A   Strassburg Christian C   Rietschel Marcella M   Altmann Heidi H   Sulk Stefan S   Thangapandi Veera Raghavan VR   Brosch Mario M   Lackner Carolin C   Stauber Rudolf E RE   Canbay Ali A   Link Alexander A   Reiberger Thomas T   Mandorfer Mattias M   Semmler Georg G   Scheiner Bernhard B   Datz Christian C   Romeo Stefano S   Ginanni Corradini Stefano S   Irving William Lucien WL   Morling Joanne R JR   Guha Indra Neil IN   Barnes Eleanor E   Ansari M Azim MA   Quistrebert Jocelyn J   Valenti Luca L   Müller Sascha A SA   Morgan Marsha Yvonne MY   Dufour Jean-François JF   Trebicka Jonel J   Berg Thomas T   Deltenre Pierre P   Mueller Sebastian S   Hampe Jochen J   Stickel Felix F  

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<h4>Objective</h4>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.<h4>Design</h4>Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recr  ...[more]