title: Interaction between PNPLA3 I148M variant and age at infection in determining fibrosis progression in chronic hepatitis C.
abstract: OBJECTIVE
  The PNPLA3 I148M sequence variant favors hepatic lipid accumulation and confers susceptibility to hepatic fibrosis and hepatocellular carcinoma. The aim of this study was to estimate the effect size of homozygosity for the PNPLA3 I148M variant (148M/M) on the fibrosis progression rate (FPR) and the interaction with age at infection in chronic hepatitis C (CHC).
  
  
  METHODS
  FPR was estimated in a prospective cohort of 247 CHC patients without alcohol intake and diabetes, with careful estimation of age at infection and determination of fibrosis stage by Ishak score.
  
  
  RESULTS
  Older age at infection was the strongest determinant of FPR (p<0.0001). PNPLA3 148M/M was associated with faster FPR in individuals infected at older age (above the median, 21 years; -0.64±0.2, n = 8 vs. -0.95±0.3, n = 166 log10 FPR respectively; p = 0.001; confirmed for lower age thresholds, p<0.05), but not in those infected at younger age (p = ns). The negative impact of PNPLA3 148M/M on fibrosis progression was more marked in subjects at risk of altered hepatic lipid metabolism (those with grade 2-3 steatosis, genotype 3, and overweight; p<0.05). At multivariate analysis, PNPLA3 148M/M was associated with FPR (incremental effect 0.08±0.03 log10 fibrosis unit per year; p = 0.022), independently of several confounders, and there was a significant interaction between 148M/M and older age at infection (p = 0.025). The association between 148M/M and FPR remained significant even after adjustment for steatosis severity (p = 0.032).
  
  
  CONCLUSIONS
  We observed an interaction between homozygosity for the PNPLA3 I148M variant and age at infection in determining fibrosis progression in CHC patients.
authors.affiliation: Department of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milano, Italy.
authors.forename: Stella
authors.initials: S
authors.lastname: De Nicola
authors.affiliation: Department of Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.affiliation: Department of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milano, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Aghemo
authors.affiliation: Virology Program, INGM - Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," Milano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cheroni
authors.affiliation: Department of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milano, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: D'Ambrosio
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Pedrazzini
authors.affiliation: Virology Program, INGM - Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," Milano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marabita
authors.affiliation: Virology Program, INGM - Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," Milano, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Donnici
authors.affiliation: Department of Pathology, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Maggioni
authors.affiliation: Department of Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milano, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
authors.affiliation: Department of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milano, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Virology Program, INGM - Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," Milano, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.affiliation: Department of Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milano, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D018450:Disease Progression; D005234:Fatty Liver / Q000150:complications / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000150:complications / Q000235:genetics*; D006801:Humans; D008049:Lipase / Q000235:genetics*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D015999:Multivariate Analysis; D020125:Mutation, Missense; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D055815:Young Adult; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent