Abstract
Keratin 8 (KRT8) is one of the major intermediate filament proteins expressed in single-layered epithelia of the gastrointestinal tract. Transgenic mice over-expressing human KRT8 display pancreatic mononuclear infiltration, interstitial fibrosis and dysplasia of acinar cells resulting in exocrine pancreatic insufficiency. These experimental data are in accordance with a recent report describing an association between KRT8 variations and chronic pancreatitis. This prompted us to investigate KRT8 polymorphisms in patients with pancreatic disorders. The KRT8 Y54H and G62C polymorphisms were assessed in a cohort of patients with acute and chronic pancreatitis of various aetiologies or pancreatic cancer originating from Austria (n=16), the Czech Republic (n=90), Germany (n=1698), Great Britain (n=36), India (n=60), Italy (n=143), the Netherlands (n=128), Romania (n=3), Spain (n=133), and Switzerland (n=129). We also studied 4,234 control subjects from these countries and 1,492 control subjects originating from Benin, Cameroon, Ethiopia, Ecuador, and Turkey. Polymorphisms were analysed by melting curve analysis with fluorescence resonance energy transfer probes. The frequency of G62C did not differ between patients with acute or chronic pancreatitis, pancreatic adenocarcinoma and control individuals. The frequency of G62C varied in European populations from 0.4 to 3.8%, showing a northwest to southeast decline. The Y54H alteration was not detected in any of the 2,436 patients. Only 3/4,580 (0.07%) European, Turkish and Indian control subjects were heterozygous for Y54H in contrast to 34/951 (3.6%) control subjects of African descent. Our data suggest that the KRT8 alterations, Y54H and G62C, do not predispose patients to the development of pancreatitis or pancreatic cancer.
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Acknowledgements
The authors thank Michael Becker, Thomas Berg, Jana Bernardova, Claudia Güldner, Werner Luck, Seraphina Serole, Bertram Wiedenmann, Ulrike Witt (Berlin), Markus Lerch, Peter Simon (Greifswald), Helmut Friess, Beat Künzli (Heidelberg), Volker Keim (Leipzig), Walter Halangk, Christiane Jechorek (Magdeburg), Wolfgang Böck (Ulm), Milan Macek Jr. (Prague), Mariette Verlaan (Nijmegen), Giovanni Destro-Bisol (Rome), Roberta Galavotti (Verona) for collecting clinical data, support and/or excellent technical assistance. The initial experiments of this study were supported by the Deutsche Forschungsgemeinschaft (Wi 2036/1-1). The study was supported by the Sonnenfeld-Stiftung (Berlin, Germany), by the Dutch foundation of Digestive Diseases (MLDS WS00-21), and by VZFNM 00064203(6112) to Milan Macek. Dr. Joost P. H. Drenth is a recipient of a NWO-VIDI grant.
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Treiber, M., Schulz, HU., Landt, O. et al. Keratin 8 sequence variants in patients with pancreatitis and pancreatic cancer. J Mol Med 84, 1015–1022 (2006). https://doi.org/10.1007/s00109-006-0096-7
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DOI: https://doi.org/10.1007/s00109-006-0096-7