HCC and liver disease risks in homozygous PNPLA3 p.I148M carriers approach monogenic inheritance
Authors: Marcin Krawczyk, Caroline S. Stokes, Stefano Romeo, Frank Lammert
Journal: Journal of Hepatology (2015)

Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinomaJournal of HepatologyVol. 61Issue 1PreviewSubtle inter-patient genetic variation and environmental factors combine to determine disease progression in non-alcoholic fatty liver disease (NAFLD). Carriage of the PNPLA3 rs738409 c.444C >G minor allele (encoding the I148M variant) has been robustly associated with advanced NAFLD. Although most hepatocellular carcinoma (HCC) is related to chronic viral hepatitis or alcoholic liver disease, the incidence of NAFLD-related HCC is increasing. We examined whether rs738409 C >G was associated with HCC-risk in patients with NAFLD. Full-Text PDF Reply to: HCC and liver disease risk in homozygous PNPLA3 p.I148M carriers approach monogenic inheritanceJournal of HepatologyVol. 62Issue 4PreviewWe read with interest the thought-provoking letter from Krawczyk et al. [1] in response to our recent publication in the Journal of Hepatology describing the strong genetic association between the PNPLA3 rs738409 (C>G, p.I148M) variant and the development of NAFLD-associated hepatocellular carcinoma (HCC) [2]. We agree that the observed magnitude of effect is striking: comparison of genotype frequencies between a NAFLD-HCC patient cohort and an unselected UK general population sample (the MRC/Wellcome Trust UK 1958 Birth Cohort) demonstrated a 12-fold increased risk of HCC [OR 12.19; 95% CI 6.89–21.58; p <0.0001] for rs738409 minor (G) allele homozygotes relative to C-allele homozygotes [2]. Full-Text PDF Open Access The study published in the Journal of Hepatology by Liu et al. [[1]Liu Y.L. Patman G.L. Leathart J.B. Piguet A.C. Burt A.D. Dufour J.F. et al.Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma.J Hepatol. 2014; 61: 75-81Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar] has robustly validated a strong genetic association between the common PNPLA3 variant p.I148M and the risk of developing hepatocellular carcinoma (HCC), in patients with non-alcoholic fatty liver disease (NAFLD), also reported previously [[2]Burza M.A. Pirazzi C. Maglio C. Sjöholm K. Mancina R.M. Svensson P.A. et al.PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals.Dig Liver Dis. 2012; 44: 1037-1041Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. The association study [[1]Liu Y.L. Patman G.L. Leathart J.B. Piguet A.C. Burt A.D. Dufour J.F. et al.Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma.J Hepatol. 2014; 61: 75-81Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar] comprised 100 individuals with NAFLD-associated HCC and 1,476 controls and showed that homozygous carriers of the p.148M mutation carry a 12-fold increased HCC risk (odds ratio [OR] = 12.19, 95% confidence interval = 6.89–21.58, p <0.0001) as compared to p.I148 homozygotes. The magnitude of this risk is remarkable and comparable to another inherited liver disease, i.e., hereditary haemochromatosis. This disease is due to HFE gene mutations and it represents a monogenic ('Mendelian') liver disorder [[3]Feder J.N. Gnirke A. Thomas W. Tsuchihashi Z. Ruddy D.A. Basava A. et al.A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.Nat Genet. 1996; 13: 399-408Crossref PubMed Scopus (3327) Google Scholar].Table 1A shows that the OR for HCC development is comparable between HFE-associated haemochromatosis and PNPLA3-associated fatty liver disease. A meta-analysis on haemochromatosis, encompassing in total 320 HCC cases and almost 2,000 controls from Europe and China [[4]Ellervik C. Birgens H. Tybjaerg-Hansen A. Nordestgaard B.G. Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls.Hepatology. 2007; 46: 1071-1080Crossref PubMed Scopus (115) Google Scholar], showed that homozygous carriers of the HFE mutation p.282Y have a 12-fold increased risk of developing liver disease (Table 1A). Interestingly, carriers of HFE and PNPLA3 mutations may develop HCC even without cirrhosis [5Kew M.C. Hepatic iron overload and hepatocellular carcinoma.Liver Cancer. 2014; 3: 31-40Crossref Scopus (125) Google Scholar, 6Krawczyk M. Portincasa P. Lammert F. PNPLA3-associated steatohepatitis: toward a gene-based classification of fatty liver disease.Semin Liver Dis. 2013; 33: 369-379Crossref PubMed Scopus (64) Google Scholar].Table 1(A) Risk of liver disease or HCC in carriers of PNPLA3 vs. HFE mutations. (B) Comparison of PNPLA3 and HFE as genetic risk factors.CI, confidence interval; HCC, hepatocellular carcinoma; NASH, non-alcoholic steatohepatitis; N, number; OR, odds ratio; p, protein. Risk allele frequencies according to http://www.ncbi.nlm.nih.gov/snp/. Open table in a new tab Overall, both PNPLA3 p.I148M and HFE p.C282Y mutations pose comparable risks for developing liver disease. Interestingly, studies showed the PNPLA3 p.148M allele has been associated with a 2- to 7-fold increased risk for fatty liver, steatohepatitis, and fibrosis [7Krawczyk M. Grünhage F. Zimmer V. Lammert F. Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastography-based study in chronic liver disease.J Hepatol. 2011; 55: 299-306Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 8Sookoian S. Pirola C.J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.Hepatology. 2011; 53: 1883-1894Crossref PubMed Scopus (655) Google Scholar]. This effect magnitude is comparable to the 4- to 10-fold increased risk of liver disease and steatohepatitis, respectively, in homozygous carriers of the HFE mutation [[4]Ellervik C. Birgens H. Tybjaerg-Hansen A. Nordestgaard B.G. Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls.Hepatology. 2007; 46: 1071-1080Crossref PubMed Scopus (115) Google Scholar] (Table 1B). Similarly, the interaction between the genetic variant and alcohol consumption promotes the development of clinically relevant liver disease for both PNPLA3 and HFE mutations [9Stickel F. Buch S. Lau K. Meyer zu Schwabedissen H. Berg T. Ridinger M. et al.Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians.Hepatology. 2011; 53: 86-95Crossref PubMed Scopus (232) Google Scholar, 10Chamorro A.J. Torres J.L. Miron-Canelo J.A. González-Sarmiento R. Laso F.J. Marcos M. Systematic review with meta-analysis: the I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is significantly associated with alcoholic liver cirrhosis.Aliment Pharmacol Ther. 2014; 40: 571-581Crossref PubMed Scopus (60) Google Scholar]. The frequency of the PNPLA3 p.I148M mutation in the general population is higher than the frequency of the HFE p.C282Y mutation (Table 1B). This results in an a priori higher chance of carrying the PNPLA3 rather than HFE variant in NAFLD-associated HCC.However, whereas HFE-associated haemochromatosis represents a well-recognized monogenic disease, PNPLA3-associated steatohepatitis currently does not. We conclude that given the remarkably high risk of HCC secondary to NAFLD for PNPLA3 p.148M homozygotes, there is a need for additional systematic studies with long-term follow-up. Finally, well-powered genetic studies to investigate the risk of HCC conferred by combinations of HFE and PNPLA3 mutations might be envisioned.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The study published in the Journal of Hepatology by Liu et al. [[1]Liu Y.L. Patman G.L. Leathart J.B. Piguet A.C. Burt A.D. Dufour J.F. et al.Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma.J Hepatol. 2014; 61: 75-81Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar] has robustly validated a strong genetic association between the common PNPLA3 variant p.I148M and the risk of developing hepatocellular carcinoma (HCC), in patients with non-alcoholic fatty liver disease (NAFLD), also reported previously [[2]Burza M.A. Pirazzi C. Maglio C. Sjöholm K. Mancina R.M. Svensson P.A. et al.PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals.Dig Liver Dis. 2012; 44: 1037-1041Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. The association study [[1]Liu Y.L. Patman G.L. Leathart J.B. Piguet A.C. Burt A.D. Dufour J.F. et al.Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma.J Hepatol. 2014; 61: 75-81Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar] comprised 100 individuals with NAFLD-associated HCC and 1,476 controls and showed that homozygous carriers of the p.148M mutation carry a 12-fold increased HCC risk (odds ratio [OR] = 12.19, 95% confidence interval = 6.89–21.58, p <0.0001) as compared to p.I148 homozygotes. The magnitude of this risk is remarkable and comparable to another inherited liver disease, i.e., hereditary haemochromatosis. This disease is due to HFE gene mutations and it represents a monogenic ('Mendelian') liver disorder [[3]Feder J.N. Gnirke A. Thomas W. Tsuchihashi Z. Ruddy D.A. Basava A. et al.A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.Nat Genet. 1996; 13: 399-408Crossref PubMed Scopus (3327) Google Scholar]. Table 1A shows that the OR for HCC development is comparable between HFE-associated haemochromatosis and PNPLA3-associated fatty liver disease. A meta-analysis on haemochromatosis, encompassing in total 320 HCC cases and almost 2,000 controls from Europe and China [[4]Ellervik C. Birgens H. Tybjaerg-Hansen A. Nordestgaard B.G. Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls.Hepatology. 2007; 46: 1071-1080Crossref PubMed Scopus (115) Google Scholar], showed that homozygous carriers of the HFE mutation p.282Y have a 12-fold increased risk of developing liver disease (Table 1A). Interestingly, carriers of HFE and PNPLA3 mutations may develop HCC even without cirrhosis [5Kew M.C. Hepatic iron overload and hepatocellular carcinoma.Liver Cancer. 2014; 3: 31-40Crossref Scopus (125) Google Scholar, 6Krawczyk M. Portincasa P. Lammert F. PNPLA3-associated steatohepatitis: toward a gene-based classification of fatty liver disease.Semin Liver Dis. 2013; 33: 369-379Crossref PubMed Scopus (64) Google Scholar]. CI, confidence interval; HCC, hepatocellular carcinoma; NASH, non-alcoholic steatohepatitis; N, number; OR, odds ratio; p, protein. Risk allele frequencies according to http://www.ncbi.nlm.nih.gov/snp/. Overall, both PNPLA3 p.I148M and HFE p.C282Y mutations pose comparable risks for developing liver disease. Interestingly, studies showed the PNPLA3 p.148M allele has been associated with a 2- to 7-fold increased risk for fatty liver, steatohepatitis, and fibrosis [7Krawczyk M. Grünhage F. Zimmer V. Lammert F. Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastography-based study in chronic liver disease.J Hepatol. 2011; 55: 299-306Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 8Sookoian S. Pirola C.J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.Hepatology. 2011; 53: 1883-1894Crossref PubMed Scopus (655) Google Scholar]. This effect magnitude is comparable to the 4- to 10-fold increased risk of liver disease and steatohepatitis, respectively, in homozygous carriers of the HFE mutation [[4]Ellervik C. Birgens H. Tybjaerg-Hansen A. Nordestgaard B.G. Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls.Hepatology. 2007; 46: 1071-1080Crossref PubMed Scopus (115) Google Scholar] (Table 1B). Similarly, the interaction between the genetic variant and alcohol consumption promotes the development of clinically relevant liver disease for both PNPLA3 and HFE mutations [9Stickel F. Buch S. Lau K. Meyer zu Schwabedissen H. Berg T. Ridinger M. et al.Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians.Hepatology. 2011; 53: 86-95Crossref PubMed Scopus (232) Google Scholar, 10Chamorro A.J. Torres J.L. Miron-Canelo J.A. González-Sarmiento R. Laso F.J. Marcos M. Systematic review with meta-analysis: the I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is significantly associated with alcoholic liver cirrhosis.Aliment Pharmacol Ther. 2014; 40: 571-581Crossref PubMed Scopus (60) Google Scholar]. The frequency of the PNPLA3 p.I148M mutation in the general population is higher than the frequency of the HFE p.C282Y mutation (Table 1B). This results in an a priori higher chance of carrying the PNPLA3 rather than HFE variant in NAFLD-associated HCC. However, whereas HFE-associated haemochromatosis represents a well-recognized monogenic disease, PNPLA3-associated steatohepatitis currently does not. We conclude that given the remarkably high risk of HCC secondary to NAFLD for PNPLA3 p.148M homozygotes, there is a need for additional systematic studies with long-term follow-up. Finally, well-powered genetic studies to investigate the risk of HCC conferred by combinations of HFE and PNPLA3 mutations might be envisioned. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.