PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases

Yang, Jie; Trépo, Eric; Nahon, Pierre; Cao, Qian; Moreno, Christophe; Letouzé, Éric; Imbeaud, Sandrine; Gustot, Thierry; Devière, Jacques; Debette, Stéphanie; Amouyel, Philippe; Bioulac‐Sage, Paulette; Caldéraro, Julien; Ganne-Carrié, Nathalie; Laurent, Alexis; Blanc, Jean Frédéric; Guyot, Erwan; Sutton, Angéla; Ziol, Marianne; Zucman‐Rossi, Jessica; Nault, Jean–Charles

doi:10.1002/ijc.31910

Cited by 85 publications

(87 citation statements)

References 50 publications

(105 reference statements)

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“…A GWAS has identified a SNP of patatin‐like phospholipase domain‐containing 3 ( PNPLA3 ) gene rs738409, which is associated with risk of development of nonalcoholic fatty liver disease (NAFLD) . Additional studies have also reported an association with risk of developing steatosis, fibrosis, and cirrhosis attributed to high alcohol intake and also with risk of HCC on alcohol‐related liver disease (ALD) . Furthermore, transmembrane 6 superfamily 2 ( TM6SF2 ) rs58542926 has also been associated with risk of NAFLD and ALD as well as HCC .…”

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confidence: 99%

“…Additional studies have also reported an association with risk of developing steatosis, fibrosis, and cirrhosis attributed to high alcohol intake and also with risk of HCC on alcohol‐related liver disease (ALD) . Furthermore, transmembrane 6 superfamily 2 ( TM6SF2 ) rs58542926 has also been associated with risk of NAFLD and ALD as well as HCC . The impact of PNPLA3 and TM6SF2 in HCC development on chronic hepatitis C (CHC) or B (CHB) seems to be marginal .…”

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confidence: 99%

“…Furthermore, transmembrane 6 superfamily 2 ( TM6SF2 ) rs58542926 has also been associated with risk of NAFLD and ALD as well as HCC . The impact of PNPLA3 and TM6SF2 in HCC development on chronic hepatitis C (CHC) or B (CHB) seems to be marginal . Interestingly, these genes are involved in lipid metabolism.…”

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confidence: 99%

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A 17‐Beta‐Hydroxysteroid Dehydrogenase 13 Variant Protects From Hepatocellular Carcinoma Development in Alcoholic Liver Disease

et al. 2019

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Recently, a loss of function variant (rs72613567) in 17‐beta‐hydroxysteroid dehydrogenase 13 (HSD17B13) has been identified as protective of nonalcoholic (NAFLD) and alcoholic liver disease (ALD). However, the role of this single‐nucleotide polymorphism (SNP) in the development of hepatocellular carcinoma (HCC) is currently unknown. A total of 3,315 European patients with HCC (n = 1,109) or without HCC, but with chronic liver disease (CLD; n = 2,206), from four centers were analyzed either by whole‐exome sequencing (WES; exploratory cohort, 285 HCC) or genotyped for HSD17B13 rs72613567 (validation cohort, 824 HCC and all CLD). We included a control group of 33,337 healthy European individuals from the Exome Aggregation Consortium. We compared distribution of genotype using the chi‐square test and logistic regression. In the exploratory cohort analyzed by WES, frequency of the TA allele of HSD17B13 rs72613567 was significantly decreased in HCC patients compared to healthy controls (P = 1.52 × 10−06). In the validation cohort, frequency of TA allele carriers was also decreased in patients with CLD and without HCC (39%) compared to healthy individuals (47%; P < 0.0001). The protective effect of the TA allele of HSD17B13 rs72613567 was identified in patients with ALD (odds ratio [OR] = 0.73; 95% confidence interval [CI], 0.65‐0.82; P < 0.0001), NAFLD (OR = 0.64; 95% CI, 0.49‐0.83; P = 0.0007), and hepatitis C (OR = 0.71; 95% CI, 0.60‐0.85; P = 0.0002). In patients with ALD, the proportion of TA allele carriers with HCC was significantly lower (32%) than in CLD patients without HCC (40%), even after adjustment for age, sex, and fibrosis (OR = 0.64; 95% CI, 0.46‐0.87; P = 0.005). Conclusion: The HSD17B13 rs72613567 loss of function variant is protective of HCC development in patients with ALD.

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A 17‐Beta‐Hydroxysteroid Dehydrogenase 13 Variant Protects From Hepatocellular Carcinoma Development in Alcoholic Liver Disease

et al. 2019

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“…In fact, while the rs738409 mutation has been convincingly associated to liver carcinogenesis in alcoholic liver disease [28,29] and in nonalcoholic steatohepatitis [30,31], this association in viral hepatitis has been the subject of controversy [32,33]. While some authors reported an increased risk of HCC development in HCV patients carrying the G allele [34][35][36][37][38], others failed to confirm these findings [4,[39][40][41][42]. The reason for this discrepancy may belong to the different ethnicities of the study populations; in fact, the largest part of the studies failing to demonstrate the association of this SNP with HCC has been conducted on Asian populations.…”

Section: Discussionmentioning

confidence: 99%

Interplay of PNPLA3 and HSD17B13 Variants in Modulating the Risk of Hepatocellular Carcinoma among Hepatitis C Patients

Benedittis

Bellan

Crevola

et al. 2020

Gastroenterology Research and Practice

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A single-nucleotide polymorphism causing a C to G change in the PNPLA3 gene (rs738409) is associated with disease severity and development of hepatocellular carcinoma (HCC) in nonalcoholic fatty liver disease; the insertion variant rs72613567:TA of the 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13) mitigates this detrimental effect. Our aim was to evaluate if the same holds true in chronic hepatitis C virus infection (HCV). With a case control retrospective study design, we selected 110 patients who developed HCC on a background of HCV infection, matching each patient for sex and age (±30 months) to three HCV-infected, non-HCC patients. All participants underwent genotyping for PNPLA3 and HSD17B13 gene variants. Both univariate and multivariate analyses of risk factors for advanced disease and HCC were performed. Carriage of PNPLA3 G∗ allele was associated with a trend of progressively more severe liver disease, from mild fibrosis to significant fibrosis, cirrhosis, and HCC (p=0.007). When the HSD17B13:TA status of these patients was taken into account, the abovementioned trend was strengthened among HSD17B13 major allele homozygotes and completely blunted among carriers of the minor allele (p=0.0003 and 0.953, respectively). In a conditional logistic regression model including diabetes and AST to platelet ratio index among predictor variables, the unfavourable genetic profile characterized by the coexistence of the PNPLA3 minor allele and HSD17B13 major allele (vs. all other possible combinations) was an independent risk factor for HCC (OR=2.00, 95% CI: 1.23-3.26) together with a history of alcohol abuse. In conclusion, carriage of the combination PNPLA3 minor allele and HSD17B13 major allele may represent a risk factor for HCC among HCV-infected patients. The interplay between the two genes may explain some of the controversy on this topic and may be exploited to stratify HCC risk in hepatitis C.

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“…The DEPDC5 rs1012068 G allele was associated with a 40% increased risk of cirrhosis, OR 95%CI (1.40: 1.08-1.81; P = 0.011) [25]. Another European study genotyped for 7 SNPs (DEPDC5 rs1012068, GRIK1 rs455804, KIF1B rs17401966, STAT4 rs7574865, MICA rs2596542, DLC1 rs2275959, and DDX18 rs2551677) in 1020 HCC, 2021 chronic liver diseases (CLD) but without HCC and 2484 healthy subjects and found also no significant association of MICA or DEPDC5 with HCC development [26]. This is indicating that the role of the DEPDC5 gene in the HCC development needs further research and validation in different ethnicities.…”

Section: Depdc5 (Rs1012068) and Hccmentioning

confidence: 99%

Main insights of genome wide association studies into HCV-related HCC

Moaz

Abdallah

Yousef

et al. 2020

Egypt Liver Journal

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Background: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-mortality globally. Hepatocarcinogenesis is a complex multifactorial process. Host genetic background appeared to play a crucial role in the progression of HCC among chronic hepatitis C patients, especially in the era of Genome Wide Association Studies (GWAS) which allowed us to study the association of millions of single nucleotide polymorphisms (SNPs) with different complex diseases. This article aimed to review the discovered SNPs associated with the risk of HCVrelated HCC development which was reported in the published GWA studies and subsequent validation studies and also try to explain the possible functional pathways. Main text: We reviewed the recent GWA studies which reported several new loci associated with the risk of HCVrelated HCC, such as (SNPs) in MHC class I polypeptide-related sequence A (MICA), DEP domain-containing 5 (DEPDC5), Tolloid-like protein 1 (TLL1), and human leukocyte antigen (HLA) genes. We also explained the possible underlying biological mechanisms that affect the host immune response pathways. Additionally, we discussed the controversial results reported by the subsequent validation studies of different ethnicities. Conclusions: Although GWA studies reported strong evidence of the association between the identified SNPs and the risk of HCV-related HCC development, more functional experiments are necessary to confirm the defined roles of these genetic mutations for the future clinical application in different populations.

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PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases

Cited by 85 publications

References 50 publications

A 17‐Beta‐Hydroxysteroid Dehydrogenase 13 Variant Protects From Hepatocellular Carcinoma Development in Alcoholic Liver Disease

A 17‐Beta‐Hydroxysteroid Dehydrogenase 13 Variant Protects From Hepatocellular Carcinoma Development in Alcoholic Liver Disease

Interplay of PNPLA3 and HSD17B13 Variants in Modulating the Risk of Hepatocellular Carcinoma among Hepatitis C Patients

Main insights of genome wide association studies into HCV-related HCC

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