Association between rs738409 polymorphism in patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene and hepatocellular carcinoma susceptibility: Evidence from case-control studies

Li, Jianfeng; Zheng, Enqi; Xie, Ming

doi:10.1016/j.gene.2018.11.012

Cited by 21 publications

(13 citation statements)

References 29 publications

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“…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. In a very recent meta-analysis, the association between HCC and rs738409 has been confirmed in Caucasians [5]. This is in line with other reports, according to which carriage of the PNPLA3 mutation is a risk factor for liver disease progression and HCC in Caucasians but not in Asians [23,43].…”

Section: Discussionsupporting

confidence: 85%

“…In fact, carriers of the G allele at the abovementioned locus have a reduction in the enzymatic activity of adiponutrin, resulting in higher intracellular triglyceride levels [3], which might then increase their risk to develop advanced fibrosis, cirrhosis, and HCC. As far as hepatitis C virus-(HCV-) infected patients are concerned, however, the association between PNPLA3 variants and HCC has been debated, suggesting that, in this condition, other factors may mask the alleged effect on hepatocarcinogenesis [4,5].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

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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“…In another study, human PNPLA3 was overexpressed and purified from HEK293 cells and showed to have a lipase activity on 1,2o-dilauryl-rac-glycerol-3-glutaric acid-(6'-methylresorufin) ester (122). Mutation of the active-site serine within the Ser 47 -Asp 166 catalytic dyad motif abolished the lipase activity; however, overexpression of human PNPLA3 in HEK293 cells did not decrease the cellular triglyceride levels (122). The recombinant human PNPLA3(148M) mutant from Sf9 cells was shown to lose the triglyceride hydrolase activity using triolein as substrate (133).…”

Section: Pnpla3 Enzymatic Activitiesmentioning

confidence: 99%

“…Hepatic accumulation of PNPLA3(148M) protein leads to triglyceride accumulation, liver injury, and fibrosis. With different etiologies, this may lead to the development of various liver disorders including NAFLD, NASH, ALD, alcoholic hepatitis (AH), cirrhosis, and HCC.reports have also shown that the 148M variant is also associated with higher risk for HCC(77, 85, 92, 93, 106, 108,153,(160)(161)(162)(163)(164)(165)(166)(167)(168)(169). In addition, the PNPLA3 variant rs738409 could lead to differential gene regulation via microRNAs.…”

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confidence: 99%

PNPLA3—A Potential Therapeutic Target for Personalized Treatment of Chronic Liver Disease

Dong

2019

Front. Med.

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Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is a lipid droplet-associated protein that has been shown to have hydrolase activity toward triglycerides and retinyl esters. The first evidence of PNPLA3 being associated with fatty liver disease was revealed by a genome-wide association study (GWAS) of Hispanic, African American, and European American individuals in the Dallas Heart Study back in 2008. Since then, numerous GWAS reports have shown that PNPLA3 rs738409[G] (148M) variant is associated with hepatic triglyceride accumulation (steatosis), inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma regardless of etiologies including alcohol-or obesity-related and others. The frequency of PNPLA3(148M) variant ranges from 17% in African Americans, 23% in European Americans, to 49% in Hispanics in the Dallas Heart Study. Due to high prevalence of obesity and alcohol consumption in modern societies, the PNPLA3(148M) gene variant and environment interaction poses a serious concern for public health, especially chronic liver diseases including alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Therefore, PNPLA3(148M) variant is a potential therapeutic target for chronic liver disease in the rs738409 allele carriers. Currently, there is no approved drug specifically targeting the PNPLA3(148M) variant yet. With additional mechanistic studies, novel therapeutic strategies are expected to be developed for the treatment of the PNPLA3(148M) variant-associated chronic liver diseases in the near future.

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“…Of note, patatin-like phospholipase domain-containing protein 3 ( PNPLA3 ), a lipase that strongly associates with NAFLD progression to NASH and HCC [209], was also found downregulated in the liver of Hep-specific ATX deletion (ATXΔHep) mice (Figure 3B). Interestingly, PNPLA3 rs738409 C>G polymorphism may increase the HCC risk in the virus and alcohol-related HCC in caucasians [210], as does for NAFLD related HCC [211]. However, it remains to be examined whether ATX through LPA directly affects PNPLA3 function.…”

Section: Deregulated Lpa Metabolism and Risk Factors For Liver Cancermentioning

confidence: 99%

Deregulated Lysophosphatidic Acid Metabolism and Signaling in Liver Cancer

Kaffe

Magkrioti

Aidinis

2019

Cancers

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Liver cancer is one of the leading causes of death worldwide due to late diagnosis and scarcity of treatment options. The major risk factor for liver cancer is cirrhosis with the underlying causes of cirrhosis being viral infection (hepatitis B or C), metabolic deregulation (Non-alcoholic fatty liver disease (NAFLD) in the presence of obesity and diabetes), alcohol or cholestatic disorders. Lysophosphatidic acid (LPA) is a bioactive phospholipid with numerous effects, most of them compatible with the hallmarks of cancer (proliferation, migration, invasion, survival, evasion of apoptosis, deregulated metabolism, neoangiogenesis, etc.). Autotaxin (ATX) is the enzyme responsible for the bulk of extracellular LPA production, and together with LPA signaling is involved in chronic inflammatory diseases, fibrosis and cancer. This review discusses the most important findings and the mechanisms related to ATX/LPA/LPAR involvement on metabolic, viral and cholestatic liver disorders and their progression to liver cancer in the context of human patients and mouse models. It focuses on the role of ATX/LPA in NAFLD development and its progression to liver cancer as NAFLD has an increasing incidence which is associated with the increasing incidence of liver cancer. Bearing in mind that adipose tissue accounts for the largest amount of LPA production, many studies have implicated LPA in adipose tissue metabolism and inflammation, liver steatosis, insulin resistance, glucose intolerance and lipogenesis. At the same time, LPA and ATX play crucial roles in fibrotic diseases. Given that hepatocellular carcinoma (HCC) is usually developed on the background of liver fibrosis, therapies that both delay the progression of fibrosis and prevent its development to malignancy would be very promising. Therefore, ATX/LPA signaling appears as an attractive therapeutic target as evidenced by the fact that it is involved in both liver fibrosis progression and liver cancer development.

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Association between rs738409 polymorphism in patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene and hepatocellular carcinoma susceptibility: Evidence from case-control studies

Cited by 21 publications

References 29 publications

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

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

PNPLA3—A Potential Therapeutic Target for Personalized Treatment of Chronic Liver Disease

Deregulated Lysophosphatidic Acid Metabolism and Signaling in Liver Cancer

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