title: Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis.
abstract: 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.
authors.affiliation: Department of Visceral Surgery and Medicine and felix.stickel@ikp.unibe.ch.
authors.forename: Felix
authors.initials: F
authors.lastname: Stickel
authors.affiliation: 1st Medical Department, University Hospital Dresden, Technical University Dresden, Dresden, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Buch
authors.affiliation: Department of Gastroenterology, University Hospital Innsbruck, Innsbruck, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Zoller
authors.affiliation: Department of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Hultcrantz
authors.affiliation: Department of Human Genetics, University Hospital Berne, Berne, Switzerland.
authors.forename: Sabina
authors.initials: S
authors.lastname: Gallati
authors.affiliation: Department of Pharmacology, Medical University Vienna, Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Österreicher
authors.affiliation: Department of Gastroenterology, University Hospital Innsbruck, Innsbruck, Austria.
authors.forename: Armin
authors.initials: A
authors.lastname: Finkenstedt
authors.affiliation: Department of Internal Medicine, Hospital Oberndorf, Salzburg, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Stadlmayr
authors.affiliation: Department of Internal Medicine, Hospital Oberndorf, Salzburg, Austria.
authors.forename: Elmar
authors.initials: E
authors.lastname: Aigner
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Enijad
authors.initials: E
authors.lastname: Sahinbegovic
authors.affiliation: Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sarrazin
authors.affiliation: Department of General and Thoracic Surgery.
authors.forename: Clemens
authors.initials: C
authors.lastname: Schafmayer
authors.affiliation: Department of General and Thoracic Surgery.
authors.forename: Felix
authors.initials: F
authors.lastname: Braun
authors.affiliation: Department of Internal Medicine I.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Erhart
authors.affiliation: Institute of Medical Informatics and Statistics and.
authors.forename: Michael
authors.initials: M
authors.lastname: Nothnagel
authors.affiliation: Department of Internal Medicine A and.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.affiliation: Department of Internal Medicine A and.
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.affiliation: Institute of Community Medicine, University of Greifswald, Greifswald, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.affiliation: Department of Human Genetics, University Hospital Berne, Berne, Switzerland.
authors.forename: André
authors.initials: A
authors.lastname: Schaller
authors.affiliation: Department of Internal Medicine I and.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kratzer
authors.affiliation: Division of Endocrinology and Diabetes, University of Ulm Medical Centre, Ulm, Germany.
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.affiliation: Institute of Pathology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Department of Biosciences and Nutrition and.
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
authors.affiliation: Department for Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Torkvist
authors.affiliation: Department of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Stal
authors.affiliation: Department of Internal Medicine I.
authors.forename: Alexander
authors.initials: A
authors.lastname: Arlt
authors.affiliation: Institute for Clinical Molecular Biology, University-Hospital Schleswig-Holstein, Kiel Campus, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Department of General and Thoracic Surgery.
authors.forename: Thomas
authors.initials: T
authors.lastname: Becker
authors.affiliation: Institute of Medical Informatics and Statistics and.
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
authors.affiliation: 1st Medical Department, Hanusch Hospital, Vienna, Austria.
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.affiliation: Department of Internal Medicine, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.affiliation: Gastroenterology Center Kiel, Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Hinrichsen
authors.affiliation: Department of Rheumatology and Immunology, Medical University of Graz, Graz, Austria and.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Krones
authors.affiliation: Department of Rheumatology and Immunology, Medical University of Graz, Graz, Austria and.
authors.forename: Christian
authors.initials: C
authors.lastname: Dejaco
authors.affiliation: First Department of Medicine, Paracelsus Private Medical University of Salzburg, Salzburg, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Strasser
authors.affiliation: Department of Internal Medicine, Hospital Oberndorf, Salzburg, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Datz
authors.affiliation: 1st Medical Department, University Hospital Dresden, Technical University Dresden, Dresden, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
mesh_terms: D000368:Aged; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006432:Hemochromatosis / Q000150:complications / Q000235:genetics* / Q000473:pathology; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013381:Subtilisins / Q000235:genetics*
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007501:Iron; C099101:PCSK7 protein, human; D013381:Subtilisins