Reevaluating the role of TRPV6 deficiency in human and mouse pancreatitis

Functionally defective genetic variants of the calcium channel transient receptor potential vanilloid type 6 (TRPV6) have been shown to markedly increase the risk for chronic pancreatitis in humans. Genetic inactivation of Trpv6 in mice worsened the severity of pancreatitis induced by secretagogue hyperstimulation. The aims of the present study were to reexamine the role of loss-of-function TRPV6 gene variants in an adult Hungarian cohort with nonalcoholic chronic pancreatitis and to characterize cerulein-induced pancreatitis in a novel Trpv6-deleted mouse strain. We found that 2.1% of chronic pancreatitis patients carried defective TRPV6 variants, whereas no such variants were identified in control subjects. Homozygous deletion of Trpv6 in C57BL/6N mice (Trpv6-KO) caused no spontaneous pancreatitis but slightly increased the severity of cerulein-induced acute pancreatitis and delayed recovery after an acute episode in a subset of mice. Cerulein-induced intrapancreatic trypsin and chymotrypsin activity was unchanged in Trpv6-KO mice relative to C57BL/6N controls. Crossing homozygous Trpv6-KO mice with heterozygous Spink1-KO mice did not result in spontaneous pancreatitis. Our results confirmed the association of defective TRPV6 variants with human chronic pancreatitis in a nonalcoholic cohort. Furthermore, we found that TRPV6 played a relatively minor role in cerulein-induced murine pancreatitis, highlighting the need for better animal models for studying human TRPV6 variants.NEW & NOTEWORTHY Prior studies indicated that defective variants of transient receptor potential vanilloid type 6 (TRPV6) encoding a constitutive calcium channel increased the risk of chronic pancreatitis in humans, and genetic inactivation of Trpv6 aggravated the severity of experimental pancreatitis in mice. We reexamined these findings by conducting a genetic case-control study and characterizing novel Trpv6-deleted mice. We confirmed the association of defective TRPV6 variants with human chronic pancreatitis but found that Trpv6 deficiency had limited impact on secretagogue-induced pancreatitis in mice.