Patatin-Like Phospholipase Domain-Containing 3 I148M... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

Patatin-Like Phospholipase Domain-Containing 3 I148M Polymorphism, Steatosis, and Liver Damage in Chronic Hepatitis Cσ

Valenti, Luca1*; Rumi, MariaGrazia2; Galmozzi, Enrico1; Aghemo, Alessio2; Del Menico, Benedetta1; De Nicola, Stella2; Dongiovanni, Paola1; Maggioni, Marco3; Fracanzani, Anna Ludovica1; Rametta, Raffaela1; Colombo, Massimo2; Fargion, Silvia1†#

1 Department of Internal Medicine, Università degli Studi, Fondazione IRCCS Ospedale Maggiore Policlinico “Ca' Granda” IRCCS, Milan, Italy

2 A.M. Migliavacca Center for Liver Disease, First Division of Gastroenterology, IRCCS, Milan, Italy

3 Pathology, Università degli Studi, Fondazione IRCCS Ospedale Maggiore Policlinico “Ca' Granda” IRCCS, Milan, Italy

*Address reprint requests to: Centro Malattie Metabolichedel Fegato, Department of Internal Medicine, Universitàdegli Studi, Ospedale Maggiore Policlinico “Ca'Granda” IRCCS, Milano, Via F Sforza 35, 20122 Milano, Italy

†CentroMalattieMetabolichedelFegato, Department of Internal Medicine,UniversitàdegliStudi,OspedaleMaggiorePoliclinico“Ca'Granda” IRCCS, Milano, Via F Sforza 35, 20122 Milano, Italy

Email:[email protected]

Received 9 October 2010; Accepted 18 November 2010

Grant sponsor: FIRST Università degli Studi di Milano 2007, 2008 (to L.V., S.F.); Ricerca corrente Ospedale Maggiore Policlinico 2006 and 2008 (to L.V., S.F.); and Centro per lo Studio delle Malattie del Fegato e del Metabolismo.

σ_Potential conflict of interest: Massimo Colombo: Grant and Research support: Schering-Plough, Roche, Novartis, Bristol Myers Squibb; Advisory committees: Schering-Plough, Roche, Novartis, Vertex, Bristol Myers Squibb, Gilead Sciences, Bayer; Speaking and Teaching: Schering-plough, Roche, Novartis, Vertex, Gilead Sciences, Bristol Myers Squibb, Bayer; Maria Grazia Rumi: Speaking and Teaching: Roche; Alessio Aghemo: Speaking and Teaching: Roche._

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Additional supporting information may be found in the online version of this article.

Abstract

Steatosis has been reported to negatively influence the natural history of chronic hepatitis C (CHC), but controversy remains over its causal role due to the confounding effect of adiposity, insulin resistance, and diabetes. The rs738409 C>G patatin-like phospholipase domain-containing 3 ( PNPLA3 ) single nucleotide polymorphism (SNP), encoding for the I148M protein variant, influences liver fat without affecting insulin resistance and body composition. The aim of this study was to evaluate the effect of the rs738409 CG genotype on liver fat and fibrosis in CHC patients. We also explored the possible effect of PNPLA3 genotype on other steatosis-related complications, namely, treatment failure and hepatocellular carcinoma (HCC) development. To this end we considered two independent series of 325 and 494 CHC patients with available DNA and liver biopsy followed at tertiary referral centers in northern Italy. The rs738409 genotype was determined by a Taqman assay. The rs738409 GG genotype, observed in 10% of patients, was associated with steatosis independently of age, sex, body mass index (BMI), diabetes, alcohol intake, and viral genotype (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.4-2.7; P < 0.001). The association with rs738409 genotype was confirmed for severe steatosis, was independent of alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) values, and was observed in all viral genotypes but the 3. The rs738409 GG genotype was associated with fibrosis stage and cirrhosis (OR 1.47, 95% CI 1.2-1.9; P = 0.002), treatment response (n = 470; OR 0.63, 95% CI 0.4-0.8; P = 0.006), and HCC occurrence (n = 325; OR 2.16, 95% CI 1.3-3.6; P = 0.002), independently of confounders. Conclusion: The rs738409 PNPLA3 genotype influences steatosis development in CHC and is independently associated with cirrhosis and other steatosis-related clinical outcomes, such as lack of response to antiviral treatment and possibly HCC. (Hepatology 2011)