TY  - JOUR
AB  - BACKGROUND/OBJECTIVES: Enhancers are key drivers of tissue-specific gene expression and can contain variants associated with pancreatic diseases. Enhancer-target gene assignment remains challenging, with the Activity-By-Contact (ABC) model, integrating open-chromatin, histone modification and chromatin interaction data, consistently outperforming other approaches. Recently an advanced version, the generalized ABC (gABC) model was published, yet lacking a clear and unique promoter definition impairing interpretability. In pancreas the model has not yet been evaluated. METHODS: We applied both basal ABC and gABC to map gene-regulatory regions to their respective candidate target genes in pancreas datasets. Next, to balance high gABC performance and ABC interpretability, we implemented the novel canonical-transcript-based and adapted ABC (caABC) model using ENSEMBL canonical transcripts. We compared the performance of all three approaches to predict gene-regulatory regions overlapping with fine-mapped pancreatic expression quantitative trait loci (eQTLs) from GTEx (V8). At the eQTL-colocalized and fine-mapped chronic pancreatitis risk locus CTRC we exemplarily evaluated predicted enhancer-promoter interactions. Finally, we provide a genome-wide unified caABC dataset of pancreatic enhancers and regulated genes. RESULTS: We demonstrate significantly improved performance of both gABC and caABC compared to ABC in the pancreas, with slightly better performance of gABC at the cost of impaired interpretability compared to caABC. At the chronic pancreatitis risk locus CTRC, caABC enhancer predictions separate fine-mapped risk-variants from high-LD non-fine-mapped variants. CONCLUSIONS: We provide a genome-wide set of pancreas-specific enhancer regions and respective target genes. Our dataset will be helpful for the prioritization of regulatory disease-causing mutations in pancreatic tissue.
AU  - Schmidt, A.W.*
AU  - Demidov, G.*
AU  - Krannich, F.*
AU  - Heinig, M.
AU  - Ossowski, S.*
AU  - Witt, H.*
AU  - Rosendahl, J.*
AU  - Laumen, H.*
C1  - 75059
C2  - 57733
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
SP  - 718-727
TI  - Genome-wide discovery of enhancer - promoter interactions in the human pancreas using an improved Activity-By-Contact-based model.
JO  - Pancreatol.
VL  - 25
IS  - 5
PB  - Elsevier
PY  - 2025
SN  - 1424-3903
ER  - 

TY  - JOUR
AB  - Background: Previous genome-wide association studies (GWAS) identified genome-wide significant risk loci in chronic pancreatitis and investigated underlying disease causing mechanisms by simple overlaps with expression quantitative trait loci (eQTLs), a procedure which may often result in false positive conclusions. Methods: We conducted a GWAS in 584 non-alcoholic chronic pancreatitis (NACP) patients and 6040 healthy controls. Next, we applied Bayesian colocalization analysis of identified genome-wide significant risk loci from both, our recently published alcoholic chronic pancreatitis (ACP) and the novel NACP dataset, with pancreas eQTLs from the GTEx V8 European cohort to prioritize candidate causal genes and extracted credible sets of shared causal variants. Results: Variants at the CTRC (p = 1.22 × 10−21) and SPINK1 (p = 6.59 × 10−47) risk loci reached genome-wide significance in NACP. CTRC risk variants colocalized with CTRC eQTLs in ACP (PP4 = 0.99, PP4/PP3 = 95.51) and NACP (PP4 = 0.99, PP4/PP3 = 95.46). For both diseases, the 95% credible set of shared causal variants consisted of rs497078 and rs545634. CLDN2-MORC4 risk variants colocalized with CLDN2 eQTLs in ACP (PP4 = 0.98, PP4/PP3 = 42.20) and NACP (PP4 = 0.67, PP4/PP3 = 7.18), probably driven by the shared causal variant rs12688220. Conclusions: A shared causal CTRC risk variant might unfold its pathogenic effect in ACP and NACP by reducing CTRC expression, while the CLDN2-MORC4 shared causal variant rs12688220 may modify ACP and NACP risk by increasing CLDN2 expression.
AU  - Schmidt, A.W.*
AU  - Kühnapfel, A.*
AU  - Kirsten, H.*
AU  - Grallert, H.
AU  - Hellerbrand, C.*
AU  - Kiefer, F.*
AU  - Mann, K.*
AU  - Mueller, S.*
AU  - Nöthen, M.M.*
AU  - Peters, A.
AU  - Ridinger, M.*
AU  - Frank, J.*
AU  - Rietschel, M.*
AU  - Soranzo, N.*
AU  - Soyka, M.*
AU  - Wodarz, N.*
AU  - Malerba, G.*
AU  - Gambaro, G.*
AU  - Gieger, C.
AU  - Scholz, M.*
AU  - Krug, S.*
AU  - Michl, P.*
AU  - Ewers, M.*
AU  - Witt, H.*
AU  - Laumen, H.*
AU  - Rosendahl, J.*
C1  - 64687
C2  - 52406
SP  - 449-456
TI  - Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms.
JO  - Pancreatol.
VL  - 22
IS  - 4
PY  - 2022
SN  - 1424-3903
ER  - 

TY  - JOUR
AU  - Kong, B.*
AU  - Bruns, P.
AU  - Behler, N.*
AU  - Schlitter, A.M.*
AU  - Friess, H.*
AU  - Erkan, M.*
AU  - Theis, F.J.
AU  - Esposito, I.*
AU  - Michalski, C.W.*
AU  - Kleeff, J.*
C1  - 50361
C2  - 42165
SP  - S. 11
TI  - Oncogenic Kras promotes early pancreatic carcinogenesis by perpetuating elements of natural inflammatory response.
JO  - Pancreatol.
VL  - 16
IS  - 1
PY  - 2016
SN  - 1424-3903
ER  - 

TY  - JOUR
AB  - Recent advances in molecular biology, biochemistry and genetics have broadened our understanding of tumourigenesis and of the maintenance and spread of pancreatic cancer far beyond traditional microscopic histopathological analysis. While the main focus of pancreatic cancer research has been on pancreatic ductal adenocarcinoma, molecular research has also led to a better understanding of rare tumours of the pancreas, as well as to the definition of previously unknown tumour entities that can only be identified through the application of molecular tools. Furthermore, molecular analysis increasingly reveals the genetic and cell biological heterogeneity of established tumour entities, making sub-classification of tumours possible. Genetic and molecular approaches may, therefore, not only lead to a better understanding of the pathogenesis of pancreatic tumours, but also culminate in more precise diagnosis as well as individually tailored treatment strategies for affected patients.
AU  - Mihaljevic, A.L.*
AU  - Esposito, I.
AU  - Michalski, C.W.*
AU  - Kleeff, J.*
AU  - Friess, H.*
C1  - 828
C2  - 26798
CY  - BASEL
SP  - 334-339
TI  - Defining new pancreatic tumour entities by molecular analysis.
JO  - Pancreatol.
VL  - 9
IS  - 4
PB  - Karger
PY  - 2009
SN  - 1424-3903
ER  -