Modulation of the effect of PNPLA3 I148M mutation on steatosis and liver damage by alcohol intake in patients with chronic hepatitis C
Authors: Luca Valenti, Massimo Colombo, Silvia Fargion
Journal: Journal of Hepatology (2011)

Distinct, alcohol-modulated effects of PNPLA3 genotype on progression of chronic hepatitis CJournal of HepatologyVol. 55Issue 3PreviewRecent large-scale genetic studies in patients with chronic hepatitis C (CHC) provide evidence for a significant role of host genetic factors in its natural course [1], response to therapy [2], and incidence of therapy-related adverse effects [3]. Recently, a variant (rs738409 G>C) within the gene coding for patatin like phospholipase domain containing-3 (PNPLA3) was found associated with liver fat content and progression of non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) [4,5]. Full-Text PDF Open AccessReply to: “Modulation of the effect of PNPLA3 I148M mutation on steatosis and liver damage by alcohol intake in patients with chronic hepatitis C”Journal of HepatologyVol. 55Issue 6PreviewPNPLA3 rs738409 and fibrosis progression in chronic hepatitis C – There is more to it than just fat! Full-Text PDF Open Access The Patatin-like phospholipase domain-containing-3 (PNPLA3) rs738409 polymorphism, encoding for the I148M protein variant, is a strong genetic determinant of hepatic fat accumulation and progressive alcoholic as well as nonalcoholic steatohepatitis in adults and children [1Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. et al.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2116) Google Scholar, 2Valenti L. Al-Serri A. Daly A.K. Galmozzi E. Rametta R. Dongiovanni P. et al.Homozygosity for the PNPLA3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease.Hepatology. 2010; 51: 1209-1217Crossref PubMed Scopus (484) Google Scholar, 3Valenti L. Alisi A. Galmozzi E. Bartuli A. Del Menico B. Alterio A. et al.I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease.Hepatology. 2010; 52: 1274-1280Crossref PubMed Scopus (225) Google Scholar, 4Tian C. Stokowski R.P. Kershenobich D. Ballinger D.G. Hinds D.A. Variant in PNPLA3 is associated with alcoholic liver disease.Nat Genet. 2009; 42: 21-23Crossref PubMed Scopus (337) Google Scholar], explaining almost a quarter of cirrhosis variability in alcoholic liver disease [[5]Stickel F. Buch S. Lau K. Zu Schwabedissen H.M. 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 (231) Google Scholar]. We and others [6Cai T. Dufour J.F. Muellhaupt B. Gerlach T. Heim M. Moradpour D. et al.Viral genotype-specific role of PNPLA3, PPARG, MTTP and IL28B in hepatitis C virus-associated steatosis.J Hepatol. 2011; 55: 529-535Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 7Valenti L. Rumi M. Galmozzi E. Aghemo A. Del Menico B. De Nicola S. et al.Patatin-Like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C.Hepatology. 2011; 53: 791-799Crossref PubMed Scopus (220) Google Scholar] have demonstrated that in patients with chronic hepatitis C (CHC), this genetic factor influences steatosis development in nongenotype 3 patients, the progression of liver damage, and susceptibility to develop cirrhosis and its complications [[8]Valenti L. Colombo M. Fargion S. PNPLA3 genotype and hepatocellular carcinoma in chronic hepatitis C.Hepatology. 2011; 53: 1777Crossref PubMed Scopus (5) Google Scholar] (Table 1).Table 1Logistic regression analysis and meta-analysis results for the association of PNPLA3 rs738409 SNP (I148M), under a recessive inheritance model, with the presence of steatosis and cirrhosis according to daily alcohol intake in 819 previously described Italian patients [7]Valenti L. Rumi M. Galmozzi E. Aghemo A. Del Menico B. De Nicola S. et al.Patatin-Like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C.Hepatology. 2011; 53: 791-799Crossref PubMed Scopus (220) Google Scholar and 494 German patients [9]Muller T. Buch S. Berg T. Hampe J. Stickel F. Distinct, alcohol-modulated effects of PNPLA3 genotype on progression of chronic hepatitis C.J Hepatol. 2011; 55: 732-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar with CHC.OR: odds ratio for the presence of homozygosity for the 148M PNPLA3 variant, adjusted for age, sex, BMI, and, only for steatosis, viral genotype 3, as in [9]Muller T. Buch S. Berg T. Hampe J. Stickel F. Distinct, alcohol-modulated effects of PNPLA3 genotype on progression of chronic hepatitis C.J Hepatol. 2011; 55: 732-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar. c.i.: Confidence interval. Steatosis: grade 1–3 vs. grade 0. Cirrhosis: Ishak stage 5–6 vs. 0–4. Abstainers: <30 g/day; at risk drinkers: ⩾20 g/day, as in [9]Muller T. Buch S. Berg T. Hampe J. Stickel F. Distinct, alcohol-modulated effects of PNPLA3 genotype on progression of chronic hepatitis C.J Hepatol. 2011; 55: 732-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar.Pooled estimates (OR, 95% c.i.) were calculated by the inverse variance method (fixed effect model) by the Review Manager v.5 software (cochrane collaboration). ∗p <0.05 for heterogeneity between studies. Open table in a new tab OR: odds ratio for the presence of homozygosity for the 148M PNPLA3 variant, adjusted for age, sex, BMI, and, only for steatosis, viral genotype 3, as in [9]Muller T. Buch S. Berg T. Hampe J. Stickel F. Distinct, alcohol-modulated effects of PNPLA3 genotype on progression of chronic hepatitis C.J Hepatol. 2011; 55: 732-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar. c.i.: Confidence interval. Steatosis: grade 1–3 vs. grade 0. Cirrhosis: Ishak stage 5–6 vs. 0–4. Abstainers: <30 g/day; at risk drinkers: ⩾20 g/day, as in [9]Muller T. Buch S. Berg T. Hampe J. Stickel F. Distinct, alcohol-modulated effects of PNPLA3 genotype on progression of chronic hepatitis C.J Hepatol. 2011; 55: 732-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar. Pooled estimates (OR, 95% c.i.) were calculated by the inverse variance method (fixed effect model) by the Review Manager v.5 software (cochrane collaboration). ∗p <0.05 for heterogeneity between studies. Muller et al. have very recently replicated the association of the PNPLA3 148M polymorphism with steatosis and cirrhosis in an independent cross-sectional study in German patients with CHC [[9]Muller T. Buch S. Berg T. Hampe J. Stickel F. Distinct, alcohol-modulated effects of PNPLA3 genotype on progression of chronic hepatitis C.J Hepatol. 2011; 55: 732-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. Interestingly, there was a significantly higher prevalence of subjects who consumed a moderate, but potentially harmful, intake of alcohol in this series than in that described in our paper, and a distinct effect of the 148M polymorphism on steatosis and liver damage according to the amount of daily alcohol intake could be observed, in that homozygosity for the 148M was associated with steatosis only in abstainers, whereas it was associated with cirrhosis only in at risk drinkers. These data led the authors to hypothesize that PNPLA3 genotype may exert a differential effect on liver damage according to alcohol consumption. As the mechanisms underpinning the detrimental effect of the 148M PNPLA3 variant in a rapidly widening range of liver diseases is still unknown, to contribute elucidating this issue we have now replicated the same analyses in our series of patients subdivided according to alcohol intake, and provide a pooled estimate of the effect of the 148M on the risk of steatosis and cirrhosis in the two combined studies. Although the effect of PNPLA3 genotype might be more evident when considering more severe steatosis [2Valenti L. Al-Serri A. Daly A.K. Galmozzi E. Rametta R. Dongiovanni P. et al.Homozygosity for the PNPLA3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease.Hepatology. 2010; 51: 1209-1217Crossref PubMed Scopus (484) Google Scholar, 7Valenti L. Rumi M. Galmozzi E. Aghemo A. Del Menico B. De Nicola S. et al.Patatin-Like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C.Hepatology. 2011; 53: 791-799Crossref PubMed Scopus (220) Google Scholar], pooled results confirm that in CHC the 148M polymorphism is associated with the presence of steatosis only in “abstainers” (<30 g alcohol/day), possibly because of the confounding effect of alcohol in moderate drinkers, but, on the contrary, is significantly associated with cirrhosis both in abstainers and in moderate drinkers, and the effect seems more marked in those who consume more than 30 g alcohol/day, as suggested by Muller et al. [[9]Muller T. Buch S. Berg T. Hampe J. Stickel F. Distinct, alcohol-modulated effects of PNPLA3 genotype on progression of chronic hepatitis C.J Hepatol. 2011; 55: 732-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. Thus, as previously suggested [[2]Valenti L. Al-Serri A. Daly A.K. Galmozzi E. Rametta R. Dongiovanni P. et al.Homozygosity for the PNPLA3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease.Hepatology. 2010; 51: 1209-1217Crossref PubMed Scopus (484) Google Scholar], the detrimental effect of the 148M PNPLA3 variant on the progression of liver damage might not be limited to predisposition to steatosis development. The discrepant results obtained in our series, as reflected by the significant heterogeneity observed between the two studies for the effect of at risk drinking on cirrhosis, may be due to the relatively small number of drinkers in Italian patients, or to other unmeasured confounders, such as additional genetic [[10]Valenti L. De Feo T. Fracanzani A.L. Fatta E. Salvagnini M. Arico S. et al.Cytotoxic T-lymphocyte antigen-4 A49G polymorphism is associated with susceptibility to and severity of alcoholic liver disease in Italian patients.Alcohol Alcohol. 2004; 39: 276-280Crossref PubMed Scopus (31) Google Scholar] and environmental factors, and possibly the prevalence of occult HBV infection. Nevertheless, these results indicate that additional studies are warranted to analyze the interaction between even moderate amounts of alcohol and PNPLA3 genotype in liver diseases. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.