Natural Genetic Variation in a Calcium Channel Linked to Chronic Pancreatitis

Natural genetic variants in a calcium-selective ion channel gene, TRPV6, appear to influence early-onset chronic pancreatitis.

Natural genetic variants in a calcium-selective ion channel gene, TRPV6 (transient receptor potential cation channel subfamily V member 6), appear to influence early-onset chronic pancreatitis (CP), according to a study published in Gastroenterology.

The authors investigated the association of early-onset CP (nonalcoholic patients aged ≤20) with natural genetic variation present in the TRPV6 gene in an international cohort of patients and in mice.

The team conducted whole-exome sequencing of DNA from a patient with idiopathic CP and from his parents, who were without CP. As confirmation studies, they then sequenced the TRPV6 region in samples from 3 independent populations: (1) in Japan (300 patients with CP and 1070 individuals from the general population as controls), (2) in France (CP, n=470; control, n=570), and (3) in Germany (CP; n=410; control n=750).

In addition, DNA constructs containing TRPV6 and associated variants were expressed in the human kidney cell line HEK293 to measure protein activity using Ca2+ imaging assays. The effect of deleting TRPV6 in a mouse model was also assessed.

In the index patients, 2 variants in TRPV6 were identified. In the samples from Japan, the case-control association study identified 33 missense and 2 nonsense variants in TRPV6. Overall, these variants were found in 4.3% (13/300) of patients with CP and in 0.1% (1/1070) of controls (0.1%) (odds ratio [OR], 48.4; 95% CI: 6.3-371.7; P= 2.4 × 10-8). Of patients with early-onset CP, 9.7% (12/124) had 1 or more of these genetic variants.

In the samples from Europe, overall, 2.0% (18/880) of patients carried 1 or more variants causing a functionally defective TRPV6 compared with none in the controls (P= 6.2 × 10-8). Functionally defective TRPV6 variants were overrepresented in French and German patients with CP compared with controls (1.9% vs 0.0%; P=.00075 and 2.2% vs 0.0%; P=.0001, respectively).

In the HEK293 cells, the team confirmed that HEK293 cells expressing several TRPV6 variants had reduced or ablated responses relative to the control (wildtype) when Ca2+ solution was applied.

Furthermore, mice with mutated TRPV6 that were given cerulein injections, to stimulate pancreatic activity, developed more severe pancreatitis than control mice with no genetic manipulations (P=.01).

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Genetic association studies necessitate additional functional confirmation studies of the associated variants and, in this case, how variation in and loss of TRPV6 function contribute to the development of pancreatitis.

The authors concluded, “[p]atients with CP not associated with alcohol consumption should be screened for TRPV6 variants. Strategies to restore TRPV6 function might be developed for treatment of CP.”


Masamune A, Kotani H, Sörgel FL, et al. Variants that affect function of calcium channel trpv6 are associated with early-onset chronic pancreatitis [published online January 10, 2020]. Gastroenterology. doi: 10.1053/j.gastro.2020.01.005