Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-onset Chronic Pancreatitis: TRPV6 and pancreatitis

Abstract Background and Aims Changes in pancreatic calcium levels affect secretion and might be involved in development of chronic pancreatitis (CP). We investigated the association of CP with the transient receptor potential cation channel subfamily V member 6 gene (TRPV6), which encodes a Ca2+-selective ion channel, in an international cohort of patients and in mice. Methods We performed whole-exome sequencing DNA from a patient with idiopathic CP and from his parents, who did not have CP. We validated our findings by sequencing DNA from 300 patients with CP (not associated with alcohol consumption) and 1070 persons from the general population in Japan (controls). In replication studies, we sequenced DNA from patients with early-onset CP (20 y or younger), not associated with alcohol consumption, from France (n=470) or Germany (n=410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca2+ imaging assays. CP was induced by repeated injections of cerulein in TRPV6mut/mut mice. Results We identified the variants c.629C>T (p.A210V) and c.970G>A (p.D324N) in TRPV6 in the index patient. Variants that affected function of the TRPV6 product were found in 13/300 cases (4.3%) and 1/1070 controls (0.1%) from Japan (OR, 48.4; 95% CI, 6.3–371.7; P=2.4 × 10-8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 controls (P=6.2 × 10-8). Variants that did not affect the function of the TRPV6 product (p.I223T and p.D324N) were overrepresented in Japanese cases vs controls (OR, 10.9; 95% CI, 4.5–25.9; P=7.4 × 10-9 for p.I223T; and P=.01 for p.D324N), whereas the p.L299Q was overrepresented in European cases vs controls (OR, 3.0; 95% CI, 1.9–4.8; P = 1.2 × 10-5). TRPV6mut/mut given cerulein developed more severe pancreatitis than control mice, demonstrated by increased levels of pancreatic enzymes, histologic alterations, and pancreatic fibrosis. Conclusions We found that patients with early-onset CP not associated with alcohol consumption carry variants in TRPV6 that affect the function of its product, perhaps by altering Ca2+ balance in pancreatic cells. TRPV6 regulates Ca2+ homeostasis and pancreatic inflammation.