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

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

In: Human Molecular Genetics, 2014, vol. 23, no. 14, p. 3883-3890

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    Titre
    • Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis
    Auteur
    • Stickel, Felix. Department of Visceral Surgery and Medicine and
    • Buch, Stephan. 1st Medical Department, University Hospital Dresden, Technical University Dresden, Dresden, Germany
    • Zoller, Heinz. Department of Gastroenterology, University Hospital Innsbruck, Innsbruck, Austria
    • Hultcrantz, Rolf. Department of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm, Sweden
    • Gallati, Sabina. Department of Human Genetics, University Hospital Berne, Berne, Switzerland
    • Österreicher, Christoph. Department of Pharmacology, Medical University Vienna, Vienna, Austria
    • Finkenstedt, Armin. Department of Gastroenterology, University Hospital Innsbruck, Innsbruck, Austria
    • Stadlmayr, Andreas. Department of Internal Medicine, Hospital Oberndorf, Salzburg, Austria
    • Aigner, Elmar. Department of Internal Medicine, Hospital Oberndorf, Salzburg, Austria
    • Sahinbegovic, Enijad. Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany
    • Sarrazin, Christoph. Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany
    • Schafmayer, Clemens. Department of General and Thoracic Surgery
    • Braun, Felix. Department of General and Thoracic Surgery
    • Erhart, Wiebke. Department of Internal Medicine I
    • Nothnagel, Michael. Institute of Medical Informatics and Statistics and
    • Lerch, Markus M.. Department of Internal Medicine A and
    • Mayerle, Julia. Department of Internal Medicine A and
    • Völzke, Henry. Institute of Community Medicine, University of Greifswald, Greifswald, Germany
    • Schaller, André. Department of Human Genetics, University Hospital Berne, Berne, Switzerland
    • Kratzer, Wolfgang. Department of Internal Medicine I and
    • Boehm, Bernhard O.. Division of Endocrinology and Diabetes, University of Ulm Medical Centre, Ulm, Germany
    • Sipos, Bence. Institute of Pathology, University Hospital Tübingen, Tübingen, Germany
    • D'Amato, Mauro. Department of Biosciences and Nutrition and
    • Torkvist, Leif. Department for Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
    • Stal, Per. Department of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm, Sweden
    • Arlt, Alexander. Department of Internal Medicine I
    • Franke, Andre. Institute for Clinical Molecular Biology, University-Hospital Schleswig-Holstein, Kiel Campus, Germany
    • Becker, Thomas. Department of General and Thoracic Surgery
    • Krawczak, Michael. Institute of Medical Informatics and Statistics and
    • Zwerina, Jochen. 1st Medical Department, Hanusch Hospital, Vienna, Austria
    • Berg, Thomas. Department of Internal Medicine, University Hospital Leipzig, Leipzig, Germany
    • Hinrichsen, Holger. Gastroenterology Center Kiel, Kiel, Germany
    • Krones, Elisabeth. Department of Rheumatology and Immunology, Medical University of Graz, Graz, Austria and
    • Dejaco, Christian. Department of Rheumatology and Immunology, Medical University of Graz, Graz, Austria and
    • Strasser, Michael. First Department of Medicine, Paracelsus Private Medical University of Salzburg, Salzburg, Austria
    • Datz, Christian. Department of Internal Medicine, Hospital Oberndorf, Salzburg, Austria
    • Hampe, Jochen. 1st Medical Department, University Hospital Dresden, Technical University Dresden, Dresden, Germany
    Type de document
    • Postprint
    Langue
    • Inglese
    Publié dans
    • Human Molecular Genetics, 2014, vol. 23, no. 14, p. 3883-3890. Oxford University Press
    Autre version électronique
    Classification
    • Santé
    Identifiant OAI-PMH
    • oai:doc.rero.ch:303299
    Summary
    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) was associated with cirrhosis or advanced fibrosis (P = 1.02 × 10−5) in the German cohort 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 = 0.014; ORallelic = 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 = 244, P = 0.00014, ORallelic = 2.84) and of males only (N = 431, P = 2.17 × 10−5, ORallelic = 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