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.
| Original language | English |
|---|---|
| Journal | Hepatology Communications |
| Volume | 6 |
| Issue number | 5 |
| Pages (from-to) | 1213-1226 |
| Number of pages | 14 |
| DOIs | |
| Publication status | Published - 05.2022 |
Funding
This research has been conducted using the UKB Resource (application number 8764). We also acknowledge the participants and investigators of the FinnGen study. We thank participants of the STOP-HCV cirrhosis study and STOP-HCV Consortium members, who are as follows: Barnes E. (University of Oxford), Ball J.K. (University of Nottingham), Brainard D. (Gilead Sciences), Burgess G. (Conatus Pharmaceuticals), Cooke G. (Imperial College, London), Dillon J. (University of Dundee), Foster G.R. (Queen Mary University of London), Gore C. (Hepatitis C Trust), Guha N. (University of Nottingham), Halford R. (Hepatitis C Trust), Whitby K. (Gilead Sciences), Holmes C. (University of Oxford), Howe A. (British Columbia Centre for Excellence), Hudson E. (University of Oxford), Hutchinson S. (Glasgow Caledonian University). Supported by the Medical Research Foundation (Viral Hepatitis Fellowship grant C0825 to H.I.), Swiss National Funds (No. 310030_169196 to F.S.), Swiss Foundation for Alcohol Research (No. 261/15 to F.S.), German Federal Ministry for Education and Research, Liver Systems Medicine Network (No. 031L0031 to J.H.), Medical Research Council (No. MR/K01532X/1 to B., Clinician Scientist Fellowship grant MR/P008348/1 to J.R.M, No. MC_UU_12014/1 to J.M.), Medical Research Foundation (No. C0365 to J.M.), Deutsche Krebshilfe (No. 70112169 to H.D.N.), European Commission European Funds for Regional Development and Regional Ministry of Economy, Science, and Digitalization (No. ZS/2018/11/95324 to A.L.), Deutsche Forschungsgemeinschaft (SFB TRR57 to P18, CRC 1382 A09 to J.T.), European Union’s Horizon 2020 Research and Innovation Programme (Galaxy, No. 668031 to J.T.; MICROB‐PREDICT, No. 825694 to J.T.; DECISION, No. 84794 to J.T.; No. 731875 to J.T.; No. 777377 to L.V.; Photonics, No. 101016726 to L.V.; and Gilead_IN‐IT‐989‐5790 to L.V.), Cellex Foundation (PREDICT to J.T.), MyFirst Grant AIRC (No. 16888 to L.V.), Ministero della Salute (No. RF‐2016‐02364358 to L.V.), Fondazione IRCCS (No. PR‐0391 to L.V., No. RC100017A to L.V.), and Cancer Research UK (No. C30358/A29725 to E.B.). Potential conflict of interest: Dr. Trebicka has received speaking and/or consulting fees from Gore, Bayer, Alexion, MSD, Gilead, Intercept, Norgine, Grifols, Versantis, and Martin Pharmaceutical. Dr. Valenti has received speaking fees from MSD, Gilead, AlfaSigma, and AbbVie; he has served as a consultant for Gilead, Pfizer, AstraZeneca, Novo Nordisk, Intercept, Diatech Pharmacogenetics, and Ionis Pharmaceuticals and received research grants from Gilead. The other authors have nothing to report.
