Association between thePNPLA3(rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data

Abstract

The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single-nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409 [G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta-analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model 5 1.77; 95% confidence interval [CI]: 1.42-2.19; P 5 2.78 3 10 27 ). This association was more pronounced in ALD (OR 5 2.20; 95% CI: 1.80-2.67; P 5 4.71 3 10 215 ) than in CHC patients (OR 5 1.55; 95% CI: 1.03-2.34; P 5 3.52 3 10 22 ). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. Conclusion: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development. (HEPATOLOGY 2014;59:2170-2177

Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis

“…A recent meta-analysis of individual patient data from candidate gene studies has shown that the PNPLA3 rs738409 G allele is also an independent risk factor for the development of HCC in this patient population [10,11]. Recently, variants in two further genes viz.…”

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

“…Despite its strong influence on hepatic steatosis of various etiologies, a significant association between PNPLA3 polymorphism and the development of HCC has been consistently found only among patients with fatty liver diseases, including ASH and NASH (Trepo et al, 2012;Guyot et al, 2013;Takeuchi et al, 2013;Liu et al, 2014;Trepo et al, 2014). Indeed, both ASH and NASH have rather similar disease spectrums, starting with fatty liver change followed by inflammation, progressive fibrosis, and finally cirrhosis.…”

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]. Finally, the American multicentric HALT-C trial did not observe a higher risk of liver cancer occurrence in individuals carrying the rs738409[G] allele [62].…”

“…These initial reports identified a significant association between rs738409[G] and HCC. However, although the results seem concordant for individuals of European descent with non-viral HCC, they remain conflicting in HCV-infected patients [53]. Table 2 shows reported positive associations according to etiology of liver disease and highlights the limitations or quality criteria allowing a critical assessment of these studies.…”

“…This led to an initial meta-analysis [53], which also had the advantage of using individual participant data. This methodologically sound approach confirmed the potential influence of PNPLA3 on liver carcinogenesis in alcoholic cirrhotic patients of European ancestry, in whom a two-fold HCC risk was observed for those bearing the rs738409 [G] allele.…”