Function of the C-36 to T polymorphism in the human cholecystokinin gene promoter

Cholecystokinin (CCK) is the most abundant neuropeptide in the mammalian brain, and in man significant quantities are expressed in all regions of the brain.(1, 2) Therefore, CCK has been implicated in a variety of CNS functions-such as feeding behavior, anxiety, analgesia and memory functions as well as psychiatric disease like panic disorder and schizophrenia (for review, see(2,3)). Recently, a number of studies have indicated that a C-36 to T transition in the CCK gene promoter Spl element(4) (Figure 1) is associated with alcoholism and withdrawal symptoms as well as panic disorder.(5-7) Moreover, it has been proposed that the polymorphism plays a direct role in the pathogenesis of the disorders by decreasing the expression and synthesis of CCK peptides. The significance of these findings is still unclear and other studies have failed to demonstrate linkage between the polymorphism and alcoholism.(8) In this study we examined the function of the C-36 to T transition in transcription of the human CCK gene. We demonstrate that substitution of the C-36 residue causes a slight reduction of Sp1 and Sp3 binding, but this has no effect on transcription in vivo. Moreover, no difference in the response to physiological stimuli was observed. Taken together the results show that the C to T polymorphism does not play a direct role in the pathogenesis of either alcoholism or panic disorder and that a putative association to these disorders is likely to be the result of co-segregation with a linked mutation.