title: Proprotein convertase 7 rs236918 associated with liver fibrosis in Italian patients with HFE-related hemochromatosis.
abstract: OBJECTIVE
  p.Cys282Tyr homozygosity is the prevalent genotype in (HFE)-related Hereditary Hemochromatosis with low penetrance and variable expression. However, liver cirrhosis and hepatocellular carcinoma remain the main causes of mortality in these patients. Detection of genetic modifiers identifying patients at risk for liver damage would be relevant for their clinical management. We evaluated proprotein convertase 7 (PCSK7) rs236918 as genetic marker of risk of liver fibrosis in an Italian cohort of p.Cys282Tyr homozygotes.
  
  
  METHODS
  Liver fibrosis was histologically assessed by Ishak score. We evaluated PCSK7 alleles and genotypes frequencies according to single or grouped staging scores: absent/mild fibrosis (stage: 0-2), moderate (stage: 3-4), and severe fibrosis/cirrhosis (stage: 5-6). Single nucleotide polymorphism genotyping was performed by restriction fragment length polymorphism or Taqman 5'-nuclease assays.
  
  
  RESULTS
  The rs236918 allele C frequency increased from stages 0-2 to 5-6 (7.1% vs 13.6%, vs 21.9%, P = 0.003). The wild-type genotype was significantly more frequent in the absent/mild fibrosis group (54.2%) compared with only 17% in patients with severe fibrosis/cirrhosis. At univariate proportional odds model, patients with GC + CC genotypes were 2.77 times (P = 0.0018) more likely to have worse liver staging scores than wild-type patients. In the adjusted analysis, odds ratio was 2.37 (P = 0.0218), and 2.56 (P = 0.0233) when the analysis was restricted to males. An exploratory mediation analysis suggested a direct effect of genotype on severe fibrosis/cirrhosis (odds ratio = 3.11, P = 0.0157), and a mild non-significant indirect effect mediated through iron accounting for 28%.
  
  
  CONCLUSIONS
  These findings confirm that PCSK7 rs236918 C allele is a risk factor for cirrhosis development in Italian patients with HFE-Hemochromatosis.
authors: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors: Sara
authors: S
authors: Pelucchi
authors: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.|Centre of Biostatistics for Clinical Epidemiology, University of Milano-Bicocca, Monza, Italy.
authors: Stefania
authors: S
authors: Galimberti
authors: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors: Federico
authors: F
authors: Greni
authors: Department of Medicine, Second Division of Gastroenterology, IRCCS, Ospedale Maggiore Policlinico, University of Milano, Milano, Italy.
authors: Raffaela
authors: R
authors: Rametta
authors: Centre for disorder of iron metabolism, S.Gerardo Hospital, Monza, Italy.
authors: Raffaella
authors: R
authors: Mariani
authors: Centre for disorder of iron metabolism, S.Gerardo Hospital, Monza, Italy.
authors: Irene
authors: I
authors: Pelloni
authors: Department of Medicine Policlinico GB Rossi, University of Verona, Verona, Italy.
authors: Domenico
authors: D
authors: Girelli
authors: Department of Medicine Policlinico GB Rossi, University of Verona, Verona, Italy.
authors: Fabiana
authors: F
authors: Busti
authors: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors: Giulia
authors: G
authors: Ravasi
authors: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.|Centre of Biostatistics for Clinical Epidemiology, University of Milano-Bicocca, Monza, Italy.
authors: Maria Grazia
authors: MG
authors: Valsecchi
authors: Department of Medicine, Second Division of Gastroenterology, IRCCS, Ospedale Maggiore Policlinico, University of Milano, Milano, Italy.
authors: Luca
authors: L
authors: Valenti
authors: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.|Centre for disorder of iron metabolism, S.Gerardo Hospital, Monza, Italy.|Consortium of Human Molecular Genetics, Monza, Italy.
authors: Alberto
authors: A
authors: Piperno
mesh_terms: D000483:Alleles; D006528:Carcinoma, Hepatocellular; D015331:Cohort Studies; D005819:Genetic Markers / Q000235:genetics*; D005838:Genotype; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007558:Italy; D008103:Liver Cirrhosis / Q000235:genetics*; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013381:Subtilisins / Q000235:genetics*
chemical_list: D005819:Genetic Markers; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; C099101:PCSK7 protein, human; D013381:Subtilisins
keywords: Ishak score; PCSK7; iron; p.Cys282Tyr; single nucleotide polymorphism