Elsevier

Journal of Hepatology

Volume 58, Issue 2, February 2013, Pages 312-318
Journal of Hepatology

Research Article
PNPLA3 rs738409, hepatocellular carcinoma occurrence and risk model prediction in patients with cirrhosis

https://doi.org/10.1016/j.jhep.2012.09.036Get rights and content

Background & Aims

Several studies have reported an association between the genetic variant rs738409 (G) in the PNPLA3 gene and the risk of cirrhosis in various liver diseases. Our purpose was to assess the influence of this polymorphism on the risk of hepatocellular carcinoma (HCC) occurrence in two distinct longitudinal cohorts of patients with cirrhosis as well as its possible usefulness in HCC-risk model prediction.

Methods

PNPLA3 rs738409 genotypes were assessed in 279 patients with alcoholic- and 253 patients with HCV-related cirrhosis. These patients were followed-up and screened for the risk of HCC, and the influence of rs738409 on the occurrence of liver cancer was assessed using the Kaplan–Meier method, then according to the multivariate Cox model.

Results

In patients with HCV-related cirrhosis, rs738409 genotypes did not influence the risk of HCC development (log-rank = 0.7) or death (log-rank = 0.2). Conversely, in patients with alcoholic cirrhosis, the rs738409 (GG) genotype was an independent risk factor for HCC occurrence (HR = 1.72 [1.21–2.45], log-rank = 0.002) as well as older age, male gender, and higher BMI. Combining these features enabled HCC-risk stratification of this population into three groups with the 6-year cumulative incidence ranging from 3.4% (low risk, n = 58), 12.2% (intermediate risk, n = 163), and 51.7% (high risk, n = 58), respectively (HR = 4.3 [2.7–6.4]; log-rank <0.0001).

Conclusions

This study provides key data that affirm the influence of the rs738409 (GG) genotype on the occurrence of HCC in patients with alcoholic cirrhosis. Its combination with clinical features refines the selection of patients at higher risk of liver cancer development.

Introduction

Liver carcinogenesis is a complex, multistep, and multifactorial process, in which both environmental and host features are implicated. Patients with cirrhosis are particularly exposed and justify periodical screening in order to detect the early development of hepatocellular carcinoma (HCC). Although epidemiological and biological features associated with the occurrence of liver cancer in these patients are well known, the identification of genetic factors that may also play an important role in liver carcinogenesis remains poorly elucidated [1].

Several recent independent genome-wide association studies have reported a single nucleotide polymorphism (rs738409 C>G), which encodes an isoleucine to methionine substitution at position 148 in the adiponutrin/patatin-like phospholipase-3 (PNPLA3) protein sequence, as a genetic factor associated with the development of hepatic steatosis [2], [3], [4]. It was secondarily validated in independent well-defined cohorts of Caucasian patients, that the rs738409 (G) allele was associated with advanced fibrosis and a higher incidence of cirrhosis, a fact that was confirmed in patients with non-alcoholic steatohepatitis [5], [6], and is highly plausible in excessive drinkers [7], [8] or individuals chronically infected by hepatitis C virus (HCV) [9], [10]. Furthermore, the same genetic variant, leading to triglyceride accumulation in hepatocytes [11], was also found independently associated with the presence of hepatocellular carcinoma (HCC) in case-control studies that included alcoholic and/or HCV-infected patients [8], [9], [12], [13], [14], [15], although results are conflicting for chronic hepatitis C (CHC) but concordant on alcoholic liver disease (ALD).

It is tempting to speculate that the same genetic trait that influences the development of steatosis and fibrosis may also exert an effect on subsequent life-threatening complications of cirrhosis, such as HCC, but this view does not take into account the role of the underlying liver disease. Currently published studies that report an association between the rs738409 (GG) genotype and HCC only describe small sample-sized case-control studies, which might not reach stable and reliable conclusions due to their potential bias and confounding factors. In this setting, only large prospective studies, conducted in well-defined cohorts, can correctly assess the association between genetic traits and the development of liver cancer.

The goal of this study was to assess the influence of PNPLA3 rs738409 on the risk of HCC occurrence in followed-up patients with cirrhosis that were regularly screened for liver cancer, taking into account both the aetiology of the underlying liver disease and the environmental features that influence their prognosis.

Section snippets

Patients

The present work was part of a prospective study conducted in cirrhotic patients that was aimed at assessing the performance of HCC screening procedures as well as the rates and risks factors of liver cancer development in the course of various liver diseases [16]. In the present study, we considered all new patients who were consecutively referred to our liver unit for diagnosis and management of cirrhosis between January 1999 and December 2007 and who fulfilled the following inclusion

Baseline characteristics and clinical outcomes

A total of 532 patients were enrolled in this study: 253 had HCV-related cirrhosis (Table 1, mean follow-up: 95 ± 6 months) and 279 had alcoholic cirrhosis (Table 2, mean follow-up: 67 ± 5 months). Patients with alcoholic cirrhosis were more often male (77.8% vs. 54.2%, p <0.0001) with a more severe liver disease at inclusion (mean Child–Pugh score: 7.7 ± 0.2 vs. 5.3 ± 0.1, p <0.0001) as compared with HCV-infected patients. They also developed a higher proportion of deaths from end-stage liver disease

Discussion

The increasing number of independent reports, highlighting the rs738409 (G) variant as a strong genetic trait associated with steatosis and fibrosis progression common to all liver diseases [7], [8], [9], [10], led to the creation of an enthusiastic concept of “PNPLA3 disease”. Indeed, these data were in line with the idea that the induced liver fat accumulation could lead to cirrhosis constitution then development of HCC independently of the causes of hepatic insult, by activating common

Financial support

This work was supported in part by grants from the Association Française pour l’Etude du Foie (AFEF) and from the Institut de recherches scientifiques sur les boissons (IREB).

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict on interest with respect to this manuscript.

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