SPINK1 gene mutations and pancreatitis in Japan.

SPINK1 can inhibit up to 20% of trypsin activity, and may constitute one major mechanism to protect the pancreas from autodigestion. In 2000, Witt et al. first recognized the association between mutations in the SPINK1 gene and chronic pancreatitis (CP), but the significance of SPINK1 gene mutation in pancreatitis and its relation to alcohol consumption remains unclear in Japan. The aim of the present paper was to clarify the incidence of SPINK1 mutations in CP patients with various etiologies in Japan and, in addition, to examine the relationship between alcohol metabolism and the polymorphisms in the key enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase-2 (ALDH2). A total of 156 patients with CP, and 165 healthy volunteers, all Japanese, were examined for the SPINK1 mutations by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. In Japan, the prevalence of [N34S; IVS1-37T > C] and [-215G > A; IVS3 + 2T > C] was significantly higher in patients with idiopathic CP (10.6% and 12.8%, respectively) than normal subjects (0.6% and 0%). The frequency of the [-215G > A; IVS3 + 2T > C] mutation in Japan was significantly higher than that reported in other populations. Concerning alcoholic CP, the [-215G > A; IVS3 + 2T > C] mutation was found in only a small number of patients (3.9%). On analysis of ADH2 and ALDH2 gene polymorphisms an association was found between ADH2*2 allele and alcoholic CP, and the ADH2*2/2*2 genotype had a tendency to increase the risk of developing pancreatic pseudocyst. In conclusion, in Japan the [-215G > A; IVS3 + 2T > C] mutation in the SPINK1 gene may form a unique genetic background for pancreatitis.