The coexistence of TRPV6 variants with other pancreatitis-associated genes affects pediatric-onset pancreatitis.

OBJECTIVES: Recently, a genetic risk for chronic pancreatitis (CP) was found to be conferred by pathogenic variants in the transient receptor potential cation channel, subfamily V, member 6 (TRPV6). Interestingly, 20-57% of patients with functionally defective TRPV6 variants have other susceptibility genes such as cationic trypsinogen (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), chymotrypsin C (CTRC), cystic fibrosis transmembrane conductance regulator (CFTR), and carboxypeptidase A1 (CPA1). In this study, we focused on pediatric patients with acute recurrent pancreatitis (ARP) or CP with at least one variant in these five genes and investigated the presence of coexisting TRPV6 mutations.

METHODS: Ninety Japanese pediatric patients (median age at first onset, 8.0 years) who had at least one variant of these five genes were enrolled in this study. DNA samples were extracted for analysis from peripheral blood leukocytes. Coding regions of TRPV6 were screened by Sanger sequencing.

RESULTS: Regardless of functional defects or non-defects in TRPV6 variants, 14 of the 90 patients (15.6%) were trans-heterozygous for TRPV6 variants [p.A18S (n=3), p.C197R (n=3), p.I223T (n=3), p.D324N (n=4), p.M418V (n=3), p.V540F (n=1), p.A606T (n=1), and p.M721T (n=3)] and the five susceptibility genes noted above. Of these variants, p.D324N, p.V540F, and p.A606T are associated with pancreatitis. Three patients had the ancestral haplotype [p.C197R + p.M418V + p.M721T].

CONCLUSIONS: Overall, four of 90 patients (4.4%) had the coexistence of clearly pathogenic TRPV6 variants with pancreatitis-associated variants. The cumulative accumulation of these genetic factors may contribute to the development of pancreatitis at a young age.