The PNPLA3 rs738409 148M/M Genotype Is a Risk Factor for Liver Cancer in Alcoholic Cirrhosis but Shows No or Weak Association in Hepatitis C Cirrhosis

Abstract

BackgroundAn isoleucine>methionine mutation at position 148 in the PNPLA3 gene (p.I148M, rs738409) has recently been identified as a susceptibility factor for liver damage in steatohepatitis. Here, we studied whether the PNPLA3 rs738409 polymorphism also affects predisposition to hepatocellular carcinoma (HCC).MethodsWe compared distributions of PNPLA3 genotypes in 80 and 81 Caucasian patients with alcoholic and hepatitis C virus (HCV)-associated HCC to 80 and 81 age- and sex-matched patients with alcohol-related and HCV-related cirrhosis without HCC, respectively. PNPLA3 genotypes in 190 healthy individuals from the same population served as reference. Potential confounders obesity, diabetes, HCV genotype and HBV co-infection were controlled by univariate and multivariate logistic regression with forward variable selection.Results PNPLA3 genotypes were in Hardy-Weinberg equilibrium for all study groups. The frequency of the 148M allele was significantly (p<0.001) increased in alcoholic cirrhosis with (53.7%) and without HCC (36.2%) but was not different between healthy controls (22.9%) and patients with cirrhosis (25.3%; p = 0.545) and HCC (30.2%; p = 0.071) due to hepatitis C. HCC risk was highest in 148M/M homozygous patients with alcoholic liver disease (odds ratio (OR) 16.8 versus healthy controls; 95% confidence interval (CI) 6.68–42.43, p<0.001). Finally, multivariate regression confirmed 148M/M homozygosity (OR 2.8; 95%-CI: 1.24–6.42; p = 0.013) as HCC risk factor in alcoholic cirrhosis. In HCV-related cirrhosis only HCV genotype 1 was confirmed as a HCC risk factor (OR 4.2; 95%-CI: 1.50–11.52; p = 0.006).ConclusionThe PNPLA3 148M variant is a prominent risk factor for HCC in patients with alcoholic cirrhosis, while its effects are negligible in patients with cirrhosis due to HCV. This polymorphism provides an useful tool to identify individuals with particularly high HCC risk in patients with alcoholic liver disease that should be taken into account in future HCC prevention studies.

Investigation of PNPLA3 and IL28B Genotypes on Diabetes and Obesity After Liver Transplantation: Insight Into Mechanisms of Disease

“…In this study the G allele frequency appears slightly higher in the liver transplant recipient population (29%) than in the general population ($21% to 25%) (14,18,19,24). However, the frequency of GG polymorphism is close to twice the normal population (which is $5%) (19,25), possibly relating to the increased risk of liver disease progression, resulting in a GG enriched population. Although some studies have suggested less of an association of PNPLA-3 polymorphisms with insulin resistance or obesity (14,18,19,26), mechanistic studies have linked glucose metabolism and obesity with PNPLA-3 stimulation and protein production in the insulin sensitive individual (24,27,28).…”

Association of PNPLA3 Polymorphism with Hepatocellular Carcinoma Development and Prognosis in Viral and Non-Viral Chronic Liver Diseases

“…Interestingly, although PNPLA3 polymorphism has been related to hepatic steatosis in patients with HCV infection, its association with HCC development is less clear with conflicting results. Some studies have demonstrated that the GG genotype effect the risk of HCC development (Falleti et al, 2011;Sato et al, 2014), while most other studies have reported no such association (Nischalke et al, 2011;Guyot et al, 2013;Friedrich et al, 2014). For patients with HBV infection, recent data reported that PNPLA3 polymorphism was independently associated with hepatic steatosis, but not with advanced fibrosis and HCC development (Vigano et al, 2013;Brouwer et al, 2015;Zampino et al, 2015).…”

“…It has been demonstrated that this SNP is related to the impairment of hepatic triglyceride hydrolysis, resulting the accumulation of triglycerides in the hepatocytes . Recent studies have shown an association between rs738409 and HCC development in NASH (Romeo et al, 2008;Valenti et al, 2013;Liu et al, 2014) and ASH (Nischalke et al, 2011;Stickel et al, 2011;Trepo et al, 2012), suggesting a carcinogenic effect by modulating lipid metabolism. However, it is not clear whether this polymorphism affects HCC development in patients with chronic viral hepatitis (Singal et al, 2014).…”

PNPLA3 gene in liver diseases

“…Indeed, only two small-sample case-control studies from Italy [32,61] initially reported a positive association between rs738409[G] and HCC in HCV-infected patients, while at least 2 others did not observe this result [55,56]. Moreover, results obtained from meta-analyses of these studies did not provide firm conclusions [16,53].…”

“…In alcoholic cirrhotic patients, the level of evidence is solid. All initial case-control studies conducted in this population reported significant associations with PNPLA3 variants, with ORs indicating increased risk [55][56][57][58]. Most studies in this field were conducted in Europe and included a homogeneous population of nearly 1,500…”