non-coding keratin variants associate with liver fibrosis progression in patients with hemochromatosis非编码角蛋白变体在血色沉着病的患者与肝纤维化的进展.pdfVIP

Non-Coding Keratin Variants Associate with Liver Fibrosis Progression in Patients with Hemochromatosis 1 . 1. 1 1 2 3 Pavel Strnad * , Ozlem Kucukoglu , Mariia Lunova , Nurdan Guldiken , Tim C. Lienau , Felix Stickel , M. Bishr Omary4 1 Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany, 2 Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charite, ¨ Universitatsmedizin Berlin, Berlin, Germany, 3 Department of Medicine I, University of Erlangen-Nuremberg, Erlangen, Germany, 4 Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America Abstract Background: Keratins 8 and 18 (K8/K18) are intermediate filament proteins that protect the liver from various forms of injury. Exonic K8/K18 variants associate with adverse outcome in acute liver failure and with liver fibrosis progression in patients with chronic hepatitis C infection or primary biliary cirrhosis. Given the association of K8/K18 variants with end- stage liver disease and progression in several chronic liver disorders, we studied the importance of keratin variants in patients with hemochromatosis. Methods: The entire K8/K18 exonic regions were analyzed in 162 hemochromatosis patients carrying homozygous C282Y HFE (hemochromatosis gene) mutations. 234 liver-healthy subjects were used as controls. Exonic regions were PCR- amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Previously- generated transgenic mice overexpressing K8 G62C were studied for their su