Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis

Felix Stickel, Stephan Buch, Heinz Zoller, Rolf Hultcrantz, Sabina Gallati, Christoph Österreicher, Armin Finkenstedt, Andreas Stadlmayr, Elmar Aigner, Enijad Sahinbegovic, Christoph Sarrazin, Clemens Schafmayer, Felix Braun, Wiebke Erhart, Michael Nothnagel, Markus M. Lerch, Julia Mayerle, Henry Völzke, André Schaller, Wolfgang KratzerBernhard O. Boehm, Bence Sipos, Mauro D'Amato, Leif Torkvist, Per Stal, Alexander Arlt, Andre Franke, Thomas Becker, Michael Krawczak, Jochen Zwerina, Thomas Berg, Holger Hinrichsen, Elisabeth Krones, Christian Dejaco, Michael Strasser, Christian Datz, Jochen Hampe

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Genome-wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity for HFE C282Y is the predominant genetic risk factor for hereditary hemochromatosis (HH) and may cause liver cirrhosis. However, this genotype has a low penetrance. Thus, detection of yet unknown genetic markers that identify patients at risk of developing severe liver disease is necessary for better prevention. Genetic loci associated with iron metabolism (TF, TMPRSS6, PCSK7, TFR2 and Chr2p14) in recent GWAS and liver fibrosis (PNPLA3) in recent meta-analysis were analyzed for association with either liver cirrhosis or advanced fibrosis in 148 German HFE C282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112 HFE C282Y homozygotes from Sweden. Only variant rs236918 in the PCSK7 gene (proprotein convertase subtilisin/kexin type 7)wasassociated with cirrhosis oradvancedfibrosis (P 5 1.02 3 1025) intheGermancohort with genotypic odds ratios of 3.56 (95% CI 1.29-9.77) for CG heterozygotes and 5.38 (95% CI 2.39-12.10) for C allele carriers. Association between rs236918 and cirrhosis was confirmed in Austrian/Swiss HFE C282Y homozygotes (P 5 0.014; ORallelic 5 1.82 (95% CI 1.12-2.95) but not in Swedish patients. Post hoc combined analyses of German/Swiss/Austrian patients with available liver histology (N 5 244, P 5 0.00014, ORallelic 5 2.84) and of males only (N 5 431, P 5 2.17 3 1025, ORallelic 5 2.54) were consistent with the premier finding. Association between rs236918 and cirrhosis was not confirmed in alcoholic cirrhotics, suggesting specificity of this genetic risk factor for HH. PCSK7 variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for the HFE C282Y mutation.

Original languageEnglish
Article numberddu076
Pages (from-to)3883-3890
Number of pages8
JournalHuman Molecular Genetics
Issue number14
Publication statusPublished - 1 Jan 2014
Externally publishedYes


  • alleles
  • phenotype
  • hemochromatosis
  • liver diseases
  • liver cirrhosis
  • fibrosis
  • hepatic fibrosis
  • genome
  • heterozygote
  • homozygote
  • genetics
  • Iron metabolism
  • genome-wide association study
  • host (organism)

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