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The rs429358 locus in apolipoprotein E is associated with hepatocellular carcinoma in patients with cirrhosis

Authors: Hamish Innes; Hans Dieter Nischalke; Indra Neil Guha; Karl Heinz Weiss; Will Irving; Daniel Gotthardt; Eleanor Barnes; +31 Authors

The rs429358 locus in apolipoprotein E is associated with hepatocellular carcinoma in patients with cirrhosis

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.

Countries
Belgium, Belgium, Italy, France, United Kingdom
Keywords

Liver Cirrhosis, hepatocellular/genetics, RC799-869, carcinoma, liver neoplasms/genetics, polymorphism, Chronic Liver Disease, MESH: Liver Neoplasms, Apolipoproteins E/genetics; Carcinoma, Hepatocellular/genetics; Genetic Predisposition to Disease; Hepatitis C/complications; Humans; Liver Cirrhosis/genetics; Liver Neoplasms/genetics; Membrane Proteins/genetics; Polymorphism, Single Nucleotide/genetics, MESH: Carcinoma, Hepatocellular, humans, single nucleotide/genetics, MESH: Polymorphism, Single Nucleotide, Liver Neoplasms, MESH: Genetic Predisposition to Disease, liver cirrhosis/genetics, Genomics, Diseases of the digestive system. Gastroenterology, MESH: Apolipoproteins E, Hepatitis C, Cirrhosis, MESH: Membrane Proteins, MESH: Liver Cirrhosis, Liver cancer, Carcinoma, Hepatocellular, apolipoproteins E/genetics, SNP, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polymorphism, Single Nucleotide, Apolipoproteins E, SDG 3 - Good Health and Well-being, Hepatitis C/complications, Genetics, Humans, Genetic Predisposition to Disease, MESH: Hepatitis C, genetic predisposition to disease, membrane proteins/genetics, MESH: Humans, Hepatology, Membrane Proteins, Généralités, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Original Articles, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, ddc: ddc:

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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
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popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
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influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
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impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
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