Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2022 May;6(5):1213-1226.
doi: 10.1002/hep4.1886. Epub 2021 Dec 27.

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

Hamish Innes  1   2   3 , Hans Dieter Nischalke  4 , Indra Neil Guha  5 , Karl Heinz Weiss  6 , Will Irving  5 , Daniel Gotthardt  7 , Eleanor Barnes  8 , Janett Fischer  9 , M Azim Ansari  8 , Jonas Rosendahl  10 , Shang-Kuan Lin  8 , Astrid Marot  11   12 , Vincent Pedergnana  13 , Markus Casper  14 , Jennifer Benselin  5 , Frank Lammert  14 , John McLauchlan  15 , Philip L Lutz  4 , Victoria Hamill  1   3 , Sebastian Mueller  16   17 , Joanne R Morling  2   5 , Georg Semmler  18   19 , Florian Eyer  20 , Johann von Felden  21 , Alexander Link  22 , Arndt Vogel  23 , Jens U Marquardt  24 , Stefan Sulk  25 , Jonel Trebicka  26   27 , Luca Valenti  28   29 , Christian Datz  19 , Thomas Reiberger  18 , Clemens Schafmayer  30 , Thomas Berg  9 , Pierre Deltenre  11   31   32 , Jochen Hampe  25   33 , Felix Stickel  34 , Stephan Buch  25
Affiliations
Meta-Analysis

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

Hamish Innes et al. Hepatol Commun. 2022 May.

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.

PubMed Disclaimer

Figures

FIG. 1
FIG. 1
Association of candidate variants with liver fat content in the UKB study.
FIG. 2
FIG. 2
Forest plot showing association between rs429358:C (APOE) and HCC. Associations are broken down into the following three categories: 1) comparing HCC to cirrhosis controls without HCC, 2) comparing HCC to population controls (who for the most part will not have liver disease), and 3) comparing alcohol HCC to individuals with an alcohol exposure but without cirrhosis or HCC. Associations are presented in terms of the LOR. An LOR of 0 indicates that the frequency of rs429358:C is the same for cases as for controls. LORs were calculated using logistic regression under an additive genetic model. Pooled effects are based on fixed‐effect meta‐analysis, weighted by effective sample size.
FIG. 3
FIG. 3
Forest plot showing association between rs2792751:T (GPAM) and HCC. Associations are broken down into the following three categories: 1) comparing HCC to cirrhosis controls without HCC, 2) comparing HCC to population controls (who for the most part will not have liver disease), and 3) comparing alcohol HCC to individuals with an alcohol exposure but without cirrhosis or HCC. Associations are presented in terms of the LOR. An LOR of 0 indicates that the frequency of rs2792751:T is the same for cases as for controls. LORs were calculated using logistic regression under an additive genetic model. Pooled effects are based on fixed‐effect meta‐analysis, weighted by effective sample size.
FIG. 4
FIG. 4
Forest plot showing association between rs2642438:A (MARC1) and HCC. Associations are broken down into the following three categories: 1) comparing HCC to cirrhosis controls without HCC, 2) comparing HCC to population controls (who for the most part will not have liver disease), and 3) comparing alcohol HCC to individuals with an alcohol exposure but without cirrhosis or HCC. Associations are presented in terms of the LOR. An LOR of 0 indicates that the frequency of rs2642438:A is the same for cases as for controls. LORs were calculated using logistic regression under an additive genetic model. Pooled effects are based on fixed‐effect meta‐analysis, weighted by effective sample size.
FIG. 5
FIG. 5
Forest plot showing association between rs187429064:G (TM6SF2) and HCC. Associations are broken down into the following three categories: 1) comparing HCC to cirrhosis controls without HCC, 2) comparing HCC to population controls (who for the most part will not have liver disease), and 3) comparing alcohol HCC to individuals with an alcohol exposure but without cirrhosis or HCC. Associations are presented in terms of the LOR. An LOR of 0 indicates that the frequency of rs187429064:G is the same for cases as for controls. LORs were calculated using logistic regression under an additive genetic model. Pooled effects are based on fixed‐effect meta‐analysis, weighted by effective sample size.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

  • Apolipoproteins: New players in cancers.
    He Y, Chen J, Ma Y, Chen H. He Y, et al. Front Pharmacol. 2022 Nov 25;13:1051280. doi: 10.3389/fphar.2022.1051280. eCollection 2022. Front Pharmacol. 2022. PMID: 36506554 Free PMC article. Review.
  • Alcohol-associated liver disease.
    Mackowiak B, Fu Y, Maccioni L, Gao B. Mackowiak B, et al. J Clin Invest. 2024 Feb 1;134(3):e176345. doi: 10.1172/JCI176345. J Clin Invest. 2024. PMID: 38299591 Free PMC article. Review.
  • Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study.
    Buch S, Innes H, Lutz PL, Nischalke HD, Marquardt JU, Fischer J, Weiss KH, Rosendahl J, Marot A, Krawczyk M, Casper M, Lammert F, Eyer F, Vogel A, Marhenke S, von Felden J, Sharma R, Atkinson SR, McQuillin A, Nattermann J, Schafmayer C, Franke A, Strassburg C, Rietschel M, Altmann H, Sulk S, Thangapandi VR, Brosch M, Lackner C, Stauber RE, Canbay A, Link A, Reiberger T, Mandorfer M, Semmler G, Scheiner B, Datz C, Romeo S, Ginanni Corradini S, Irving WL, Morling JR, Guha IN, Barnes E, Ansari MA, Quistrebert J, Valenti L, Müller SA, Morgan MY, Dufour JF, Trebicka J, Berg T, Deltenre P, Mueller S, Hampe J, Stickel F. Buch S, et al. Gut. 2023 Feb;72(2):381-391. doi: 10.1136/gutjnl-2022-327196. Epub 2022 Jul 4. Gut. 2023. PMID: 35788059 Free PMC article.
  • High producer variant of lipoprotein lipase may protect from hepatocellular carcinoma in alcohol-associated cirrhosis.
    Schmalz F, Fischer J, Innes H, Buch S, Möller C, Matz-Soja M, von Schönfels W, Krämer B, Langhans B, Klüners A, Soyka M, Stickel F, Nattermann J, Strassburg CP, Berg T, Lutz P, Nischalke HD. Schmalz F, et al. JHEP Rep. 2023 Jan 25;5(4):100684. doi: 10.1016/j.jhepr.2023.100684. eCollection 2023 Apr. JHEP Rep. 2023. PMID: 36879887 Free PMC article.

References

    1. Asrani SK, Devarhbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol 2019;70:151‐171. - PubMed
    1. Muller M, Bird TG, Nault JC. The landscape of gene mutations in cirrhosis and hepatocellular carcinoma. J Hepatol 2020;72:990‐1002. - PubMed
    1. Stickel F, Lutz P, Buch S, Nischalke HD, Silva I, Rausch V, et al. Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers. Hepatology 2020;72:88‐102. - PubMed
    1. Stickel F, Buch S, Nischalke HD, Weiss KH, Gotthardt D, Fischer J, et al. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol‐related cirrhosis. Am J Gastroenterol 2018;113:1475‐1483. Erratum in: Am J Gastroenterol 2018;113:1099. - PubMed
    1. Trepo E, Romeo S, Zucman‐Rossi J, Nahon P. PNPLA3 gene in liver diseases. J Hepatol 2016;65:399‐412. - PubMed

Publication types

MeSH terms