Reply to: “Modulation of the effect of PNPLA3 I148M mutation on steatosis and liver damage by alcohol intake in patients with chronic hepatitis C”
Authors: Felix Stickel, Eric Trépo, Christophe Moreno, Jochen Hampe
Journal: Journal of Hepatology (2011)

Modulation of the effect of PNPLA3 I148M mutation on steatosis and liver damage by alcohol intake in patients with chronic hepatitis CJournal of HepatologyVol. 55Issue 6PreviewThe 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 [1–4], explaining almost a quarter of cirrhosis variability in alcoholic liver disease [5]. We and others [6,7] 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] (Table 1). Full-Text PDF Open AccessDistinct, 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 Access PNPLA3 rs738409 and fibrosis progression in chronic hepatitis C – There is more to it than just fat!To the Editor:The Hepatology community has seen a substantial rise in publications reporting data on genetic risk factors conferring risk to fibrosis progression in non-alcoholic, alcoholic, and chronic hepatitis C-related liver diseases. For long, hypothesis-driven, often single-centre genetic case control studies have reported associations of certain candidate genes with fibrosis/cirrhosis which could not be replicated. With genome-wide association studies (GWAS) becoming a standard tool in translational research, novel candidate genes enter the stage which have been identified by systematic screening experiments [[1]Zimmer V. Lammert F. Genetics in liver disease: new concepts.Curr Opin Gastroenterol. 2011; 27: 231-239Crossref PubMed Scopus (20) Google Scholar]. GWAS make use of a hypothesis-free, or rather – hypothesis-generating approach, and have the potential to uncover genetic risk factors which had not been considered based on our previous pathophysiological understanding. A striking example for such revelation is the gene coding for patatin-like phospholipase domain containing-3 (PNPLA3; adiponutrin) of which a polymorphic variant (rs738409 G >C) was found associated with liver fat content in a landmark GWAS [[2]Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. et al.Genetic variation in PNPLA3 confers susceptibility to non-alcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2140) Google Scholar], and subsequently with progression of non-alcoholic fatty liver disease (NAFLD) [[3]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 (488) Google Scholar], and alcoholic liver disease (ALD) [4Stickel 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 (232) Google Scholar, 5Trépo E. Gustot T. Degré D. Lemmers A. Verset L. Demetter P. et al.Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease.J Hepatol. 2011; 54: 906-912Abstract Full Text Full Text PDF Scopus (126) Google Scholar] by means of candidate case control studies. The role of PNPLA3 rs738409 as a risk factor for progressive fibrosis can now be extended to chronic hepatitis C. Only in 2011, four studies presented data on the role of PNPLA3 rs738409 G which unanimously confirm that carriage of at least one allele increases the risk of advanced fibrosis and cirrhosis [6Müller 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: 729-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 7Valenti L. Rumi M.G. Galmozzi E. Aghemo A. Del Menico B. De Nicola S. et al.PNPLA3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C.Hepatology. 2011; 53: 791-799Crossref PubMed Scopus (220) Google Scholar, 8Cai 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, 9Trépo E. Pradat P. Potthoff A. Momozawa Y. Quertinmont E. Gustot T. et al.Impact of PNPLA3 (rs738409 C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C.Hepatology. 2011; 54: 60-69Crossref PubMed Scopus (154) Google Scholar] (Table 1). Our own data indicate that this association is particularly evident in hepatitis C virus-infected individuals who regularly drink alcohol as opposed to abstainers [[6]Müller 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: 729-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. Regarding the latter, PNPLA3 rs738409 G appears to modulate fat storage in the liver by a yet unknown mechanism, possibly by interaction of PNPLA3 with viral epitopes. Indeed, from the data presented in published studies, it becomes clear that PNPLA3 rs738409 G neither aggravates steatosis nor fibrosis in patients with genotype 3, supporting the hypothesis that mostly genotype 1-specific interactions with PNPLA3 are involved.Table 1Genetic candidate gene association studies on the role of PNPLA3 rs738409 G as a risk factor for fibrosis and cirrhosis. Open table in a new tab In this issue of the Journal, Valenti and coworkers have undertaken a pooled analysis of our [[6]Müller 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: 729-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] and their data [[7]Valenti L. Rumi M.G. Galmozzi E. Aghemo A. Del Menico B. De Nicola S. et al.PNPLA3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C.Hepatology. 2011; 53: 791-799Crossref PubMed Scopus (220) Google Scholar] after stratifying their patients into “at-risk” drinkers (daily alcohol consumption ⩾20 g) and abstainers [[10]Valenti L. Colombo M. Fargion S. Modulation of the effect pf PNPLA3 I148M mutation on steatosis and liver damage by alcohol intake in patients with chronic hepatitis C.J Hepatol. 2011; 55: 1471-1472Abstract Full Text Full Text PDF Scopus (0) Google Scholar]. Hereby, they confirm that carriage of PNPLA3 rs738409 G is a risk factor for steatosis in abstainers, but not in at risk drinkers, possibly due to a confounding effect on steatosis by concomitant alcohol consumption. In addition, by increasing the numbers of total cases and controls, they convincingly show that PNPLA3 rs738409 G is also a risk factor for cirrhosis in abstainers, with an additional increase of the odds ratio (OR) in at risk drinkers. Of note, a subgroup analysis of our latest data [[9]Trépo E. Pradat P. Potthoff A. Momozawa Y. Quertinmont E. Gustot T. et al.Impact of PNPLA3 (rs738409 C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C.Hepatology. 2011; 54: 60-69Crossref PubMed Scopus (154) Google Scholar], confirmed these observations [6Müller 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: 729-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 10Valenti L. Colombo M. Fargion S. Modulation of the effect pf PNPLA3 I148M mutation on steatosis and liver damage by alcohol intake in patients with chronic hepatitis C.J Hepatol. 2011; 55: 1471-1472Abstract Full Text Full Text PDF Scopus (0) Google Scholar]. Again, only abstainers were at risk of steatosis (OR = 4.52 95% confidence interval [CI] 1.32–15.48, p= 0.016). Moreover, PNPLA3 rs738409 G remained associated with advanced fibrosis in abstainers (OR = 2.68 95% CI 1.18–6.06, p= 0.018), but still its impact on fibrosis was stronger in “at-risk” drinkers (OR = 10.34 95% CI 1.15–93.16, p= 0.037). In our view, these analyses provide a perfect example of host-environment interactions in which the risk of developing cirrhosis increases in a “dose-dependent” manner with the number of risk factors present (PNPLA3 rs738409 G, hepatitis C virus, and alcohol).Together, data from these four independent studies deliver strong evidence for a significant role of PNPLA3 rs738409 for progressive liver disease not only in NAFLD and ALD, but also in CHC. What needs to be elucidated now is to decipher the cross-talk between PNPLA3 (and its genetic variation) and fibrosis-related intracellular signalling. Fat accumulation may do harm in hepatitis C infected subjects – but as we know from NAFLD, it requires a “second hit” to cause inflammation and fibrosis.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. PNPLA3 rs738409 and fibrosis progression in chronic hepatitis C – There is more to it than just fat! To the Editor: The Hepatology community has seen a substantial rise in publications reporting data on genetic risk factors conferring risk to fibrosis progression in non-alcoholic, alcoholic, and chronic hepatitis C-related liver diseases. For long, hypothesis-driven, often single-centre genetic case control studies have reported associations of certain candidate genes with fibrosis/cirrhosis which could not be replicated. With genome-wide association studies (GWAS) becoming a standard tool in translational research, novel candidate genes enter the stage which have been identified by systematic screening experiments [[1]Zimmer V. Lammert F. Genetics in liver disease: new concepts.Curr Opin Gastroenterol. 2011; 27: 231-239Crossref PubMed Scopus (20) Google Scholar]. GWAS make use of a hypothesis-free, or rather – hypothesis-generating approach, and have the potential to uncover genetic risk factors which had not been considered based on our previous pathophysiological understanding. A striking example for such revelation is the gene coding for patatin-like phospholipase domain containing-3 (PNPLA3; adiponutrin) of which a polymorphic variant (rs738409 G >C) was found associated with liver fat content in a landmark GWAS [[2]Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. et al.Genetic variation in PNPLA3 confers susceptibility to non-alcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2140) Google Scholar], and subsequently with progression of non-alcoholic fatty liver disease (NAFLD) [[3]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 (488) Google Scholar], and alcoholic liver disease (ALD) [4Stickel 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 (232) Google Scholar, 5Trépo E. Gustot T. Degré D. Lemmers A. Verset L. Demetter P. et al.Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease.J Hepatol. 2011; 54: 906-912Abstract Full Text Full Text PDF Scopus (126) Google Scholar] by means of candidate case control studies. The role of PNPLA3 rs738409 as a risk factor for progressive fibrosis can now be extended to chronic hepatitis C. Only in 2011, four studies presented data on the role of PNPLA3 rs738409 G which unanimously confirm that carriage of at least one allele increases the risk of advanced fibrosis and cirrhosis [6Müller 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: 729-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 7Valenti L. Rumi M.G. Galmozzi E. Aghemo A. Del Menico B. De Nicola S. et al.PNPLA3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C.Hepatology. 2011; 53: 791-799Crossref PubMed Scopus (220) Google Scholar, 8Cai 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, 9Trépo E. Pradat P. Potthoff A. Momozawa Y. Quertinmont E. Gustot T. et al.Impact of PNPLA3 (rs738409 C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C.Hepatology. 2011; 54: 60-69Crossref PubMed Scopus (154) Google Scholar] (Table 1). Our own data indicate that this association is particularly evident in hepatitis C virus-infected individuals who regularly drink alcohol as opposed to abstainers [[6]Müller 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: 729-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. Regarding the latter, PNPLA3 rs738409 G appears to modulate fat storage in the liver by a yet unknown mechanism, possibly by interaction of PNPLA3 with viral epitopes. Indeed, from the data presented in published studies, it becomes clear that PNPLA3 rs738409 G neither aggravates steatosis nor fibrosis in patients with genotype 3, supporting the hypothesis that mostly genotype 1-specific interactions with PNPLA3 are involved. In this issue of the Journal, Valenti and coworkers have undertaken a pooled analysis of our [[6]Müller 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: 729-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar] and their data [[7]Valenti L. Rumi M.G. Galmozzi E. Aghemo A. Del Menico B. De Nicola S. et al.PNPLA3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C.Hepatology. 2011; 53: 791-799Crossref PubMed Scopus (220) Google Scholar] after stratifying their patients into “at-risk” drinkers (daily alcohol consumption ⩾20 g) and abstainers [[10]Valenti L. Colombo M. Fargion S. Modulation of the effect pf PNPLA3 I148M mutation on steatosis and liver damage by alcohol intake in patients with chronic hepatitis C.J Hepatol. 2011; 55: 1471-1472Abstract Full Text Full Text PDF Scopus (0) Google Scholar]. Hereby, they confirm that carriage of PNPLA3 rs738409 G is a risk factor for steatosis in abstainers, but not in at risk drinkers, possibly due to a confounding effect on steatosis by concomitant alcohol consumption. In addition, by increasing the numbers of total cases and controls, they convincingly show that PNPLA3 rs738409 G is also a risk factor for cirrhosis in abstainers, with an additional increase of the odds ratio (OR) in at risk drinkers. Of note, a subgroup analysis of our latest data [[9]Trépo E. Pradat P. Potthoff A. Momozawa Y. Quertinmont E. Gustot T. et al.Impact of PNPLA3 (rs738409 C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C.Hepatology. 2011; 54: 60-69Crossref PubMed Scopus (154) Google Scholar], confirmed these observations [6Müller 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: 729-733Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 10Valenti L. Colombo M. Fargion S. Modulation of the effect pf PNPLA3 I148M mutation on steatosis and liver damage by alcohol intake in patients with chronic hepatitis C.J Hepatol. 2011; 55: 1471-1472Abstract Full Text Full Text PDF Scopus (0) Google Scholar]. Again, only abstainers were at risk of steatosis (OR = 4.52 95% confidence interval [CI] 1.32–15.48, p= 0.016). Moreover, PNPLA3 rs738409 G remained associated with advanced fibrosis in abstainers (OR = 2.68 95% CI 1.18–6.06, p= 0.018), but still its impact on fibrosis was stronger in “at-risk” drinkers (OR = 10.34 95% CI 1.15–93.16, p= 0.037). In our view, these analyses provide a perfect example of host-environment interactions in which the risk of developing cirrhosis increases in a “dose-dependent” manner with the number of risk factors present (PNPLA3 rs738409 G, hepatitis C virus, and alcohol). Together, data from these four independent studies deliver strong evidence for a significant role of PNPLA3 rs738409 for progressive liver disease not only in NAFLD and ALD, but also in CHC. What needs to be elucidated now is to decipher the cross-talk between PNPLA3 (and its genetic variation) and fibrosis-related intracellular signalling. Fat accumulation may do harm in hepatitis C infected subjects – but as we know from NAFLD, it requires a “second hit” to cause inflammation and fibrosis. 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.