Genetic Basis of Chronic Pancreatitis

Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas. The common causes of CP are toxins (alcohol and smoking), hereditary, and idiopathic. Whitcomb et al first reported R122H mutation in the cationic trypsinogen gene (PRSS1) in hereditary pancreatitis. Other common mutations in the PRSS1 gene include N29I, R116C, A16V etc. Genetic mutations are the most likely cause of idiopathic CP. Mutations in 3 important genes i.e. CFTR, SPINK1, and CTRC have been strongly implicated in the pathogenesis of idiopathic CP. In 1998, higher frequency of minor CFTR mutations was shown in patients with idiopathic CP compared with controls in Caucasians. CFTR mutations/polymorphisms have also been associated with idiopathic CP in non-Caucasian patients. In a study of Indian patients with idiopathic CP, we found minor mutations in the CFTR gene were 5 times more common compared with controls and six novel variants were detected. In a Japanese study of 65 patients with CP, a high association of Q1352H (12.3% in CP patients vs. 3.7% in controls) and R1453W (6.2% vs. 3.1%) mutations in the CFTR gene was found. In 2000, 3 studies reported significantly higher frequency of a N34S mutation in exon 3 of the SPINK1 gene in patients with idiopathic CP. We have shown that 42% of Indian patients with CP had SPINK1 mutation. In Japanese and Korean patients, IVS3 + 2T>C mutation in the SPINK1 gene was significantly higher in patients with non-alcoholic idiopathic CP. A meta-analysis on SPINK1 mutation in CP had shown that this mutation was detected in 469 of 4,842 patient alleles and in 96 of 9,714 control alleles yielding a pooled odds ratio of 11.00 (95% CI 7.59-15.93). Chymotrypsinogen C (CTRC) degrades trypsinogen and its loss-of-function variants were found in European patients with CP. In Indian patients with idiopathic CP, c.180 C>T mutation in the CTRC gene was found to be significantly higher in patients with CP (odds ratio=2.1). A hypothesis independent approach through genome wide association studies (GWAS) identified loci at X-linked CLDN2/MORC4 being associated with recurrent acute pancreatitis and alcohol-related CP in subjects of European ancestry. Subsequent studies have confirmed the association of these loci with idiopathic CP in Chinese and Indians. These observations suggest that a more meaningful term such as chronic pancreatitis-G (G denotes genetic) may be appropriate in the majority of cases of idiopathic CP.