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The role of pancreas divisum (PD) as a cause of acute recurrent or chronic pancreatitis (AR/CP) is still a matter of debate.The aims of this study were to evaluate the frequency of PD diagnosed using magnetic resonance cholangiopancreatography (MRCP) in patients with AR/CP of unknown origin (n=40) after careful exclusion of all known causes and to test the hypothesis of an interaction between anatomical (PD) and functional genetic anomalies (SPINK1,PRSS1, orCFTRgene mutations or polymorphisms (n=19, 25, and 30, respectively)) that could result in AR/CP. Patients with alcohol-induced pancreatitis (n=29) and subjects who had MRCP for a nonpancreatic disease (n=45) served as controls.PD frequency was 7% in subjects without pancreatic disease, 7% in patients with alcohol-induced pancreatitis, and 5, 16, 16, and 47% in those with idiopathic, andPRSS1-,SPINK1-, andCFTR-associated pancreatitis, respectively (P<0.0001). There was no significant difference between idiopathic pancreatitis and the two control groups. The frequency of PD was higher in patients withCFTRgene-associated pancreatitis as compared with those with idiopathic and alcoholic pancreatitis (P<0.0001) and with those withSPINK1andPRSS1gene-associated pancreatitis (P<0.02).The frequency of PD was not different in patients with idiopathic pancreatitis as compared with controls, demonstrating that PD by itself is not a cause of pancreatitis. PD frequency was higher in patients with genetic pancreatitis, especially in those withCFTRmutations or polymorphisms, suggesting a cumulative effect of these two cofactors.