Interaction between IL28B and PNPLA3 genotypes in the pathogenesis of steatosis in chronic hepatitis C non genotype-3 patients
Authors: Luca Valenti, Alessio Aghemo, Albert Friedrich Stättermayer
Journal: Journal of Hepatology (2012)

Beneficial IL28B genotype associated with lower frequency of hepatic steatosis in patients with chronic hepatitis CJournal of HepatologyVol. 55Issue 6PreviewIL28B polymorphisms have been associated with both treatment induced and spontaneous clearance of hepatitis C virus (HCV). We previously found that LDL cholesterol levels were higher in chronic hepatitis C (CHC) patients with the CC genotype at the rs12979860 polymorphism, located proximal to the IL28 gene. Here we analyzed the association of steatosis with IL28B genotype in treatment naïve patients with CHC. Full-Text PDF Reply to: "Interaction between IL28B and PNPLA3 genotypes in the pathogenesis of steatosis in chronic hepatitis C non genotype-3 patients"Journal of HepatologyVol. 56Issue 5PreviewWe thank Dr. Valenti et al. for raising an additional point that PNPLA3 might be associated with steatosis in the setting of HCV infection after controlling for IL28B [1]. They demonstrate in their cohort of 567 treatment naïve patients that both IL28B (rs12979860) and PNPLA3 (rs738409) may contribute to steatosis. Furthermore, in their study the beneficial effect of IL28B was limited to the patients without the PNPLA3 risk allele "G" as rs738409. A role of PNPLA3 GG genotype for steatosis in HCV infected patients has been observed in several studies, especially when excluding genotype 3 patients [2–5]. Full-Text PDF Open Access Steatosis is frequently observed in patients with chronic hepatitis C (CHC), and is associated with fibrosis progression and treatment failure [1Leandro G. Mangia A. Hui J. Fabris P. Rubbia-Brandt L. Colloredo G. et al.Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data.Gastroenterology. 2006; 130: 1636-1642Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar, 2Marabita F. Aghemo A. De Nicola S. Rumi M.G. Cheroni C. Scavelli R. et al.Genetic variation in the interleukin-28B gene is not associated with fibrosis progression in patients with chronic hepatitis C and known date of infection.Hepatology. 2011; 54: 1127-1134Crossref PubMed Scopus (114) Google Scholar]. Tillmann et al. recently reported a negative association between the interleukin 28B (IL28B) rs12979860 CC genotype, predicting sustained virological response [[3]Ge D. Fellay J. Thompson A.J. Simon J.S. Shianna K.V. Urban T.J. et al.Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.Nature. 2009; 461: 399-401Crossref PubMed Scopus (3114) Google Scholar], and steatosis in genotype-1 CHC [[4]Tillmann H.L. Patel K. Muir A.J. Guy C.D. Li J.H. Lao X.Q. et al.Beneficial IL28B genotype associated with lower frequency of hepatic steatosis in patients with chronic hepatitis C.J Hepatol. 2011; 55: 1195-1200Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar]. However, whether this association was independent of other genetic factors was not evaluated. The patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism is a strong determinant of hepatic fat accumulation and steatohepatitis [5Romeo 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 (2309) Google Scholar, 6Valenti 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 (513) Google Scholar], but also influences steatosis and fibrosis progression in CHC [7Cai 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 (93) Google Scholar, 8Valenti 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 (223) Google Scholar, 9Trepo 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 (156) Google Scholar]. A previous study [[7]Cai 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 (93) Google Scholar] also reported an association between IL28B rs12980275 genotype and steatosis in CHC non genotype-3 patients, but the rs12979860 IL28B polymorphism was not tested and the interaction with PNPLA3 genotype was not analyzed in details. We now confirm the negative association of rs12979860 CC with histologically-determined steatosis (111/184, 60% vs. 266/383, 69%; p= 0.036) and steatosis grade >1 (17/184, 9% vs. 70/383 18%; p= 0.0059) in 567 naïve, consecutive, non genotype-3 patients from referral centers in Milan and Vienna, without excessive alcohol intake (i.e. >60/40 g/day for M/F), HBsAg positivity, and HIV infection. Sixty-five percent of patients were genotype-1, and 20% had cirrhosis. A similar trend was observed for all genotypes. Importantly, as shown in Table 1, the association between IL28B genotype and steatosis was independent of acquired risk factors, and of the PNPLA3 GG genotype. Interestingly however, the rs12979860 CC genotype protected form steatosis in patients positive, but not in those negative for the PNPLA3 G variant at risk (49/78, 63% vs. 144/187, 77%, p= 0.022, and 62/106, 58% vs. 74/196, 62%, p= 0.52, respectively). Therefore, data suggest the possibility that an interaction occurs between IL28B and PNPLA3 genotypes in the pathogenesis of steatosis in CHC non genotype-3 patients.Table 1Independent predictors of steatosis in 567 non genotype-3 CHC patients. Open table in a new tab Evaluation of the combined effect of IL28B and PNPLA3 genotypes on treatment outcomes may permit to discriminate whether steatosis has indeed a causal role in determining resistance to antivirals, or the association is an epiphenomenon due to the confounding association of steatosis with IL28B rs12979860 CC, as suggested by Tillmann et al. [[4]Tillmann H.L. Patel K. Muir A.J. Guy C.D. Li J.H. Lao X.Q. et al.Beneficial IL28B genotype associated with lower frequency of hepatic steatosis in patients with chronic hepatitis C.J Hepatol. 2011; 55: 1195-1200Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar]. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.