title: The association of variants in PNPLA3 and GRP78 and the risk of developing hepatocellular carcinoma in an Italian population.
abstract: Hepatocellular carcinoma (HCC) has one of the worst prognoses amongst all malignancies. It commonly arises in patients with established liver disease and the diagnosis often occurs at an advanced stage. Genetic variations, such as single nucleotide polymorphisms (SNPs), may alter disease risk and thus may have use as predictive markers of disease outcome. The aims of this study were (i) to assess the association of two SNPs, rs430397 in GRP78 and rs738409 in PNPLA3 with the risk of developing HCC in a Sicilian association cohort and, (ii) to use a machine learning technique to establish a predictive combinatorial phenotypic model for HCC including rs430397 and rs738409 genotypes and clinical and laboratory attributes. The controls comprised of 304 healthy subjects while the cases comprised of 170 HCC patients the majority of whom had hepatitis C (HCV)-related cirrhosis. Significant associations were identified between the risk of developing HCC and both rs430397 (p=0.0095) and rs738409 (p=0.0063). The association between rs738409 and HCC was significantly stronger in the HCV positive cases. In the best prediction model, represented graphically by a decision tree with an acceptable misclassification rate of 17.0%, the A/A and G/A genotypes of the rs430397 variant were fixed and combined with the three rs738409 genotypes; the attributes were age, sex and alcohol. These results demonstrate significant associations between both rs430397 and rs738409 and HCC development in a Sicilian cohort. The combinatorial predictive model developed to include these genetic variants may, if validated in independent cohorts, allow for earlier diagnosis of HCC.
authors.affiliation: Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Balasus
authors.affiliation: Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Way
authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Bioinformatics Unit, San Giovanni Rotondo (FG), Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Fusilli
authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Bioinformatics Unit, San Giovanni Rotondo (FG), Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Mazza
authors.affiliation: Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK.
authors.forename: Marsha Y
authors.initials: MY
authors.lastname: Morgan
authors.affiliation: Institute of Biomedicine and Molecular Immunology, National Research Council (C.N.R.), Palermo, Italy.
authors.forename: Melchiorre
authors.initials: M
authors.lastname: Cervello
authors.affiliation: Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
authors.forename: Lydia
authors.initials: L
authors.lastname: Giannitrapani
authors.affiliation: Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Soresi
authors.affiliation: Immunohematology and Transfusion Medicine Unit, "Civico" Reference Regional Hospital, Palermo, Italy.
authors.forename: Rosalia
authors.initials: R
authors.lastname: Agliastro
authors.affiliation: Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK.|Center for Translational Medicine (CTM), International Clinical Research Center (ICRC), St. Anne's University Hospital, Brno, Czech Republic.
authors.forename: Manlio
authors.initials: M
authors.lastname: Vinciguerra
authors.affiliation: Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.|Institute of Biomedicine and Molecular Immunology, National Research Council (C.N.R.), Palermo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Montalto
mesh_terms: D000368:Aged; D000483:Alleles; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D015331:Cohort Studies; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012802:Sicily; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008049:Lipase; D008565:Membrane Proteins; C000717247:HSPA5 protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
keywords: genetic variants; hepatitis C virus; hepatocellular carcinoma; risk factors; single nucleotide polymorphisms