Su1332 CFTR, PRSS1, and SPINK1 Variants in Japanese Patients With Pancreatitis

Abstract

Background: Cystic fibrosis (CF) is an autosomal recessive disease caused by variants in the CFTR gene. To date, over 1,700 variants in CFTR have been identified. The incidence of CF in Japanese is very low (1 per 350,000 live births) compared with Caucasian (1 per 3,000 live births). The most common variants of CFTR gene in Caucasian, such as F508del, are rare in Japanese. The profiles of CFTR variants in Japanese are different from those of Caucasian. Several genes, such as cationic trypsinogen (PRSS1) and serine protease inhibitor Kazal type 1 (SPINK1), play an important role in pancreatitis susceptibility, but the roles of CFTR variants in pancreatitis have been unclear in Japan. IVS8-5T, p.Q1352H, and p.R1453W in the CFTR gene were reported to be found frequently in Asian population and affected the function of the CFTR protein. Previous studies in the Japanese population reported an association between these variants and pancreatitis, but they were analyzed at a small scale. Methods: This study was approved by the ethics committee of Tohoku University Graduate School of Medicine. A total of 482 patients (271 chronic pancreatitis (CP), 211 acute pancreatitis (AP)) and 440 controls were enrolled in this study. p.Q1352H and p.R1453W in the CFTR gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). IVS8-5T in the CFTR gene was analyzed by SNP genotyping with Real-Time PCR and direct sequencing. PRSS1 and SPINK1 variants were analyzed by PCR-RFLP and direct sequencing. Results: p.Q1352H in the CFTR gene was found in 17 (6.3%) of 271 patients with CP, 13 (6.2%) of 211 with AP, and 19 (4.3%) of 440 controls. p.R1453W in the CFTR gene was found in 16 (5.9%) of 271 with CP, 6 (2.8%) of 211 with AP, and 16 (3.6%) of 440 controls. IVS8-5T in the CFTR gene was found in 10 (3.7%) of 271 with CP, 11 (5.2%) of 211 with AP, and 15 (3.9%) of 385 controls. The CFTR variants were not significantly associated with CP (p=0.20, odds ratio (OR) 1.4, 95% confidence interval (CI) 0.9-2.1) or with AP (p=0.52, OR 1.2, 95%CI 0.71.9). p.R122H and p.N29I in the PRSS1 gene were found in 8 (4.7%) and 1 (0.6%) of 170 with CP, respectively. PRSS1 variants were not found in 440 controls. The PRSS1 variants were significantly associated with CP (p,0.01, OR 49.2, 95%CI 4.9-494.1). p.N34S and c.194+2T.C in the SPINK1 gene were found in 19 (7.0%) and 17 (6.3%) of 271 with CP, respectively. SPINK1 variants were found in 2 (0.05%) of 440 controls. The SPINK1 variants were significantly associated with CP (p,0.001, OR 30.4, 95%CI 8.0-115.4). Conclusions: PRSS1 and SPINK1 had a strong association with CP. But, the accumulation of CFTR variants in pancreatitis was less pronounced than previous studies in Japan.