The rs429358 Locus in Apolipoprotein E Is Associated With Hepatocellular Carcinoma in Patients With Cirrhosis

Innes, Hamish; Nischalke, Hans Dieter; Guha, Indra Neil; Weiss, Karl Heinz; Irving, Will; Gotthardt, Daniel; Barnes, Eleanor; Fischer, Janett; Ansari, Azim; Rosendahl, Jonas; Shang-Kuan, Lin; Marot, Astrid; Pedergnana, Vincent; Casper, Markus; Benselin, Jennifer; Lammert, Frank; McLauchlan, John; Lutz, Philip L; Hamill, Victoria; Mueller, Sebastian; Morling, Joanne R.; Semmler, Georg; Eyer, Florian; von Felden, Johann; Link, Alexander; Vogel, Arndt; Marquardt, Jens U; Sulk, Stefan; Trebicka, Jonel; Valenti, Luca; Datz, Christian; Reiberger, Thomas; Schafmayer, Clemens; Berg, Thomas; Deltenre, Pierre; Hampe, Jochen; Stickel, Felix; Buch, Stephan

Abstract

The host genetic background for hepatocellular carcinoma (HCC) is incompletely understood. We aimed to determine if four germline genetic polymorphisms, rs429358 in apolipoprotein E (APOE), rs2642438 in mitochondrial amidoxime reducing component 1 (MARC1), rs2792751 in glycerol-3-phosphate acyltransferase (GPAM), and rs187429064 in transmembrane 6 superfamily member 2 (TM6SF2), previously associated with progressive alcohol-related and nonalcoholic fatty liver disease, are also associated with HCC. Four HCC case-control data sets were constructed, including two mixed etiology data sets (UK Biobank and FinnGen); one hepatitis C virus (HCV) cohort (STOP-HCV), and one alcohol-related HCC cohort (Dresden HCC). The frequency of each variant was compared between HCC cases and cirrhosis controls (i.e., patients with cirrhosis without HCC). Population controls were also considered. Odds ratios (ORs) associations were calculated using logistic regression, adjusting for age, sex, and principal components of genetic ancestry. Fixed-effect meta-analysis was used to determine the pooled effect size across all data sets. Across four case-control data sets, 2,070 HCC cases, 4,121 cirrhosis controls, and 525,779 population controls were included. The rs429358:C allele (APOE) was significantly less frequent in HCC cases versus cirrhosis controls (OR, 0.71; 95% confidence interval [CI], 0.61-0.84; P=2.9×10−5). Rs187429064:G (TM6SF2) was significantly more common in HCC cases versus cirrhosis controls and exhibited the strongest effect size (OR, 2.03; 95% CI, 1.45-2.86; P=3.1×10−6). In contrast, rs2792751:T (GPAM) was not associated with HCC (OR, 1.01; 95% CI, 0.90-1.13; P=0.89), whereas rs2642438:A (MARC1) narrowly missed statistical significance (OR, 0.91; 95% CI, 0.84-1.00; P=0.043). Conclusion: This study associates carriage of rs429358:C (APOE) with a reduced risk of HCC in patients with cirrhosis. Conversely, carriage of rs187429064:G in TM6SF2 is associated with an increased risk of HCC in patients with cirrhosis.

Citation

Innes, H., Nischalke, H. D., Guha, I. N., Weiss, K. H., Irving, W., Gotthardt, D., …Buch, S. (2022). The rs429358 Locus in Apolipoprotein E Is Associated With Hepatocellular Carcinoma in Patients With Cirrhosis. Hepatology Communications, 6(5), 1213-1226. https://doi.org/10.1002/hep4.1886

• Journal Article Type: Article
• Acceptance Date: Nov 24, 2021
• Online Publication Date: Dec 27, 2021
• Publication Date: 2022-05
• Deposit Date: Dec 15, 2021
• Publicly Available Date: Dec 27, 2021
• Journal: Hepatology Communications
• Electronic ISSN: 2471-254X
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Issue: 5
• Pages: 1213-1226
• DOI: https://doi.org/10.1002/hep4.1886
• Keywords: Liver cancer; SNP; Cirrhosis; Genetics; Genomics; Chronic Liver Disease
• Public URL: https://nottingham-repository.worktribe.com/output/6913464
• Publisher URL: https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep4.1886