Genetic Risk contribution to Alcoholic chronic Pancreatitis (GRAP study)
Zusammenfassung der Projektergebnisse
Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas leading to irreversible damage of the organ. In the Western world alcohol abuse is the predominant contributor. However, only 5 % of heavy alcohol consumers develop CP. To evaluate the genetic contributors to alcoholic CP we conducted a genome-wide association study (GWAS) and aimed to identify SNPs and genetic loci associated with alcohol-related CP (ACP) in Europe. We established the PanEuropean working group on alcohol-related chronic pancreatitis and collected in total 2.812 patients samples throughout Europe. These include 635 samples of non-alcohol-related CP patients. All samples were screened with the Illumina Human Express Omni Bead Chip. Population-based control chip data from Germany and Europe as well as chip data of German alcohol dependent patients were obtained by collaborations and have been transferred to our center. The final analyses of the data have not been conducted throughly so far. In the meantime the data are in preparation for the analyses at the Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig. Preliminary results display the quality of our data, since we can replicate associated SNPs on a genome wide level at the PRSS1-locus and are able to depict new associated variants. This is further supported by the fact, that we were able to refine the association of SNPs within the PRSS1- locus and the CLDN2-MORC4-locus. After identificiation of new risk loci further analyses of these regions will be conducted. Functional analyses (e.g. promoter analysis) as well as biostatistical analyses (e.g. transcription factor binding sites (TFBS) to identify cis-regulatory variants will be applied.
Projektbezogene Publikationen (Auswahl)
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Genetic analyses of heme oxygenase 1 (HMOX1) in different forms of pancreatitis. PLoS One. 2012;7:e37981
Weis S, Jesinghaus M, Kovacs P, Schleinitz D, Schober R, Ruffert C, Herms M, Wittenburg H, Stumvoll M, Blüher M, Grützmann R, Schulz HU, Keim V, Mössner J, Bugert P, Witt H, Drenth JP, Krohn K, Rosendahl J
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CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2013;62:582-592
Rosendahl J, Landt O, Bernadova J, Kovacs P, Teich N, Bödeker H, Keim V, Ruffert C, Mössner J, Kage A, Stumvoll M, Groneberg D, Krüger R, Luck W, Treiber M, Becker M, Witt H
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Variants in CPA1 are strongly associated with early-onset chronic pancreatitis. Nat Genet. 2013;45:1216-1220
Witt H, Beer S, Rosendahl J, Chen JM, Chandak GR, Masamune A, Bence M, Szmola R, Oracz G, Macek M Jr, Bhatia E, Steigenberger S, Lasher D, Bühler F, Delaporte C, Tebbing J, Ludwig M, Pilsak C, Saum K, Bugert P, Masson E, Paliwal S, Bhaskar S, Sobczynska- Tomaszewska A, Bak D, Balascak I, Choudhuri G, Nageshwar Reddy D, Rao GV, Thomas V, Kume K, Nakano E, Kakuta Y, Shimosegawa T, Durko L, Szabó A, Schnúr A, Hegyi P, Rakonczay Z Jr, Pfützer R, Schneider A, Groneberg DA, Braun M, Schmidt H, Witt U, Friess H, Algül H, Landt O, Schuelke M, Krüger R, Wiedenmann B, Schmidt F, Zimmer KP, Kovacs P, Stumvoll M, Blüher M, Müller T, Janecke A, Teich N, Grützmann R, Schulz HU, Mössner J, Keim V, Löhr M, Férec C, Sahin-Tóth M
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Polymorphisms at PRSS1– PRSS2 and CLDN2–MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study. Gut. 2014
Derikx MH, Kovacs P, Scholz M, Masson E, Chen JM, Ruffert C, Lichtner P, te Morsche R, Cavestro GM, Férec C, Drenth JPH, Witt H, Rosendahl J
