Genetic analysis of pancreatic duct hyperplasia in Otsuka Long-Evans Tokushima Fatty rats: Possible association with a region on rat chromosome 14 that includes the disrupted cholecystokinin-A receptor gene

An Otsuka Long-Evans Tokushima Fatty (OLETF) strain of rat spontaneously de veloped hyperglycemia, hyperinsulinemia, insulin resistance and mild obesit y, which had been studied as animal model for type II diabetes mellitus (T2 DM). Recently, we observed that this strain coincidentally developed atypic al hyperplasia of the choledocho-pancreatic ductal epithelium with a comple te incidence. In an effort to locate genes responsible for this hyperplasia , we prepared 288 backcross progeny from a mating between OLETF rats and BN rats (which do not develop hyperplasia), and performed a genome-wide scan using 207 polymorphic genetic markers. We observed a prominent association of hyperplasia with a region involving a marker locus D14Mit4 (P = 0.00020, Fisher's exact test) and Cckar (the cholecystokinin-A receptor gene; P = 0 .00025, Fisher's exact test) which is known to be disrupted in an OLETF str ain. Our findings indicated that epithelial hyperplasia of the choledocho-p ancreatic duct is associated with a region on rat chromosome 14 around the Cckar gene in an additive fashion with another two susceptible loci, each o n chromosome 9 and 7. This implied the possibility that Cckar deficiency co uld result in a predisposition towards pancreatic duct hyperplasia.