Regional replication, refinement and functional characterisation of GWAs variants in alcoholic and non-alcoholic chronic pancreatitis

• Applicant: Professor Dr. Jonas Rosendahl
• Subject Area: Gastroenterology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 321033801

Chronic pancreatitis (CP) is a progressive inflammatory disease characterized by recurrent episodes or persisting abdominal pain that can lead to exocrine and/or endocrine insufficiency. Due to incidence rates of 3.5-10 per 100.000 inhabitants CP is a huge debit for health care and social systems. The most predominant contributors are alcohol abuse and smoking. In patients without these contributors several genetic associations have been described, however, in up to 50% of these patients no underlying genetic determinants can be identified. To elucidate common genetic variants associated with alcohol-related CP (ACP) and non alcohol-related CP (NACP) we have conducted a genome wide association (GWA) study in 2,813 CP patients. In ACP we identified five association signals with genome wide significance including two novel loci in CTRB1/CTRB2 as well as in EIF3A. To refine these associations and to characterise the functional consequences we will investigate the complex CTRB1/CTRB2 locus with Sanger sequencing technology. In NACP we will investigate the 30 best GWAs SNPs with a p-value of >1 x 10-5 with multiplex methods in a second cohort of patients and controls to identify new risk loci. We have performed complex biostatistical analyses including transcription binding site patterns of cis-regulatory elements and will characterize the functional properties of seven variants in the CTRB1/CTRB2 locus in vitro in distinct cell types. Further variants of the EIF3A locus and variants associated with NACP will be analysed in addition. With our strategy we will gain new insights in the pathogenesis of CP and explain the functional consequences of associated variants.

• DFG Programme: Research Grants