TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population

Abstract

Chronic pancreatitis (CP) is a progressive fibroinflammatory syndrome of the pancreatic tissue caused by genetic and environmental factors. Previously reported susceptibility genes in CP explain less than half of the apparent heritability. To uncover novel pathogenic mechanisms, we initially performed low‐coverage whole‐genome sequencing on 464 Chinese CP patients and 504 controls. The transient receptor potential cation channel, Subfamily V, Member 6 (TRPV6) gene was found to be significantly associated with CP after a burden test of aggregated rare nonsynonymous variants with a combined annotation dependent depletion score > 20 (p = .020). In the replication stage, we analyzed the entire coding sequence and exon/intron boundaries of the TPRV6 gene by Sanger sequencing in another 205 patients with CP and 105 controls. Integration of the findings from the two stages resulted in the identification of 25 TRPV6 variants: 1 rare nonsense variant, 20 rare missense variants, and 4 common missense variants. Loss‐of‐function variants, as determined by intracellular Ca2+ concentration in transfected HEK293T cells, were significantly overrepresented in patients as compared to controls (9/669 [1.35%] vs. 1/609 [0.16%]; odds ratio = 8.29; p = .022). This study provides evidence suggesting that TRPV6 is a novel susceptibility gene for CP.

The reversion variant (p.Arg90Leu) at the evolutionarily adaptive p.Arg90 site in CELA3B predisposes to chronic pancreatitis

“…Chronic pancreatitis (CP) is a complex disease that can be caused by genetic and/or environmental factors 1-3 . Since the mapping and cloning of the first gene found to underlie hereditary pancreatitis (i.e., PRSS1 ; MIM# 276000) more than 20 years ago 4-7 , multiple additional genes/loci associated with CP have been identified, either by means of candidate gene approaches 8-17 or hypothesis-free (‘agnostic’) approaches 18-22 .…”

Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole

“…Decreased mRNA and protein levels of TRPV6 have been found in placentas of women suffering from pre-eclampsia 25 . Several human TRPV6 gene mutations have been recently linked to transient neonatal hyperparathyroidism, skeletal under-mineralization and dysplasia, and chronic pancreatitis 26 – 32 . Because of the central role of calcium in cancer development 33 , TRPV6 has also been classified as an oncochannel that is involved in both increased cell proliferation and inhibition of apoptosis 34 , and overexpressed in various types of human cancer, including breast, prostate, colon, ovarian, thyroid, endometrial cancers, and leukemia 33 , 35 .…”

Genetic Risk Factors in Early-Onset Nonalcoholic Chronic Pancreatitis: An Update

“…In 2020, two research groups showed that loss of function variants of TRPV6 are associated with risk of chronic pancreatitis in patients from Japan, Germany, France and China [26,27]. During our research towards identification of novel CP susceptibility genes using a whole exome sequencing approach, we also found overrepresentation of the novel defective TRPV6 variants in Polish CP pediatric patients (data unpublished, [75]).…”

“…In nonalcoholic early-onset CP, TRPV6 variants contribute to disease pathogenesis in 1.5-4% of the patients [26,27]. Since it is speculated that TRPV6 plays a role in Ca 2+ removal from the ducts, the loss-of-function variants could cause elevated ductal Ca 2+ concentration, which would stimulate autoactivation of trypsinogen and increased trypsin activity.…”