Genetics of alcoholic chronic pancreatitis

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Chronic pancreatitis (CP) is a recurring inflammatory disorder of the pancreas with alcohol misuse being the most predominant risk factor. Whereas in patients without alcohol misuse (non-alcoholic CP, NACP) several genetic variants have been captured as risk factors, genetic associations in alcoholic CP (ACP) are rare. This is an interesting finding since only a small percentage of alcohol misuser develops ACP indicating further etiological factors. Recently, a genome-wide association study (GWAs) identified common variants in the PRSS1- and the CLDN2-MORC4 locus to be associated with CP. This finding was replicated in a large European cohort in that association was strongest in the ACP group and in Japanese and Indian CP patients. Functional studies demonstrated that the PRSS1 promoter variant rs4726576 (c.-204C>A) reduces transcription which results in lower intra-pancreatic trypsinogen levels. The mechanism of action of the CLDN2-MORC4 risk variants still remains to some extent unclear although it changes the localization of claudin-2 in carriers. We have conducted a large genome-wide association study in European patients with alcoholic CP and identified new risk loci that have been characterized on a functional level.

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