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.

Genetic variation inTERTmodifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study

“…Significant associations have also been identified between rs72613567 in HSD17B13 and rs429358 in APOE and a reduced risk for developing HCC in ArC 9–11. In this study, these protective associations were confirmed but failed to reach a detectable genome-wide significance level (online supplemental table 5).…”

“…In recent years, interest has focused on dissecting the underlying host genetics of HCC through candidate gene association studies. In the studies undertaken to date, loci in the genes coding for patatin-like phospholipase domain containing 3 ( PNPLA3 ; rs738409) and transmembrane 6 superfamily member 2 ( TM6SF2; rs58542926) were robustly confirmed to increase the risk of developing HCC in ArC,8 while loci, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 ( HSD17B13 ) and rs429358:C in apolipoprotein E ( APOE ), were found to attenuate risk 9–11. As the products of these genes are involved in lipid turnover and processing, it is not surprising that the same loci also modulate the risk for HCC development in people with non-alcoholic fatty liver disease (NAFLD) 12…”

Apolipoproteins: New players in cancers

“…Besides, the polymorphism of APOE has been investigated in liver cancer. Innes et al found that rs429358 of APOE is associated with a decreased risk of developing HCC in patients with liver cirrhosis (Innes et al, 2022). The E4 allele of APOE can function as a protective factor in reducing inflammation and liver fibrosis in HCV-infected patients, which may decrease the risk of liver cancer (Nascimento et al, 2021).…”

Melatonin alleviates PM2.5‐induced glucose metabolism disorder and lipidome alteration by regulating endoplasmic reticulum stress

“…ApoE is present on the surface of lipoprotein particles and plays a key role in regulating lipid transport of the liver. Carrying ApoE is associated with a reduced risk of hepatocellular carcinoma that is causally related to liver metabolic disorders 22 . Thus, intense efforts have been made to investigate hepatic metabolism based on ApoE −/− mice 23–25 .…”

“…Carrying ApoE is associated with a reduced risk of hepatocellular carcinoma that is causally related to liver metabolic disorders. 22 Thus, intense efforts have been made to investigate hepatic metabolism based on ApoE −/− mice. [23][24][25] In addition, Narjes et al proved that Empagliflozin alleviates NAFLD in high-fat diet-fed ApoE −/− mice by reducing ER stress and activating autophagy.…”