Brief Article
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World J Gastroenterol. Jun 14, 2012; 18(22): 2813-2820
Published online Jun 14, 2012. doi: 10.3748/wjg.v18.i22.2813
Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis
Luca Valenti, Paolo Maggioni, Alberto Piperno, Raffaela Rametta, Sara Pelucchi, Raffaella Mariani, Paola Dongiovanni, Anna Ludovica Fracanzani, Silvia Fargion
Luca Valenti, Paolo Maggioni, Raffaela Rametta, Paola Dongiovanni, Anna Ludovica Fracanzani, Silvia Fargion, Università degli Studi di Milano, Fondazione Ca’ Granda IRCCS Ospedale Maggiore Policlinico, 20122 Milano, Italy
Alberto Piperno, Sara Pelucchi, Raffaella Mariani, Università di Milano Bicocca, Ospedale San Gerardo Monza, 20090 Monza MI, Italy
Author contributions: Valenti L designed the study, performed the statistical analysis, drafted the manuscript and funded the study; Maggioni P, Rametta R, Pelucchi S, Mariani R, Dongiovanni P and Fracanzani AL acquired and interpreted the data and revised the manuscript for critical content; Piperno A and Fargion S interpreted the data, revised the manuscript for critical content and funded the study; all authors read, revised and approved the final version of the manuscript.
Supported by FIRST Università degli Studi di Milano 2007, 2008 to Valenti L, Fargion S; Ricerca corrente Ospedale Maggiore Policlinico 2006 and 2008 to Valenti L, Fargion S; Centro per lo Studio delle Malattie del Fegato e del Metabolismo
Correspondence to: Luca Valenti, MD, Università degli Studi di Milano, Fondazione Ca’ Granda IRCCS, Ospedale Maggiore Policlinico, via F Sforza, 20122 Milano, Italy. luca.valenti@unimi.it
Telephone: +39-2-50320278 Fax: +39-2-50320296
Received: June 27, 2011
Revised: February 22, 2012
Accepted: February 26, 2012
Published online: June 14, 2012
Abstract

AIM: To investigate whether the patatin-like phospholipase domain containing-3 gene (PNPLA3) I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis (HH).

METHODS: We studied 174 consecutive unrelated homozygous for the C282Y HFE mutation of HH (C282Y+/+ HH) patients from Northern Italy, for whom the presence of cirrhosis could be determined based on histological or clinical criteria, without excessive alcohol intake (< 30/20 g/d in males or females) or hepatitis B virus and hepatitis C virus viral hepatitis. Steatosis was evaluated in 123 patients by histology (n = 100) or ultrasound (n = 23). The PNPLA3 rs738409 single nucleotide polymorphism, encoding for the p.148M protein variant, was genotyped by a Taqman assay (assay on demand, Applied Biosystems). The association of the PNPLA3 I148M protein variant (p.I148M) with steatosis, fibrosis stage, and cirrhosis was evaluated by logistic regression analysis.

RESULTS: PNPLA3 genotype was not associated with metabolic parameters, including body mass index (BMI), the presence of diabetes, and lipid levels, but the presence of the p.148M variant at risk was independently associated with steatosis [odds ratio (OR) 1.84 per p.148M allele, 95% confidence interval (CI): 1.05-3.31; P = 0.037], independently of BMI and alanine aminotransaminase (ALT) levels. The p.148M variant was also associated with higher aspartate aminotransferase (P = 0.0014) and ALT levels (P = 0.017) at diagnosis, independently of BMI and the severity of iron overload. In patients with liver biopsy, the 148M variant was independently associated with the severity (stage) of fibrosis (estimated coefficient 0.56 ± 0.27, P = 0.041). In the overall series of patients, the p.148M variant was associated with cirrhosis in lean (P = 0.049), but not in overweight patients (P = not significant). At logistic regression analysis, cirrhosis was associated with BMI ≥ 25 (OR 1.82, 95% CI: 1.02-3.55), ferritin > 1000 ng/mL at diagnosis (OR 19.3, 95% CI: 5.3-125), and with the G allele in patients with BMI < 25 (OR 3.26, 95% CI: 1.3-10.3).

CONCLUSION: The PNPLA3 I148M polymorphism may represent a permissive factor for fibrosis progression in patients with C282Y+/+ HH.

Keywords: Fatty liver; Fibrosis; Hemochromatosis; HFE protein; Iron overload; Patatin-like phospholipase domain containing-3 gene; Steatosis