Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis.

Adolescent Adult Age of Onset Aged Animals Calcium / metabolism Calcium Channels / genetics Child Child, Preschool DNA Mutational Analysis Disease Models, Animal Female HEK293 Cells Humans INDEL Mutation Infant Infant, Newborn Male Mice Mice, Transgenic Middle Aged Pancreas / pathology Pancreatitis, Chronic / genetics Polymorphism, Single Nucleotide TRPV Cation Channels / genetics Exome Sequencing Young Adult

Genetics Next-generation Sequencing Transient Receptor Potential Whole Exome Sequencing

Journal

Gastroenterology

ISSN: 1528-0012

Titre abrégé: Gastroenterology

Pays: United States

ID NLM: 0374630

Informations de publication

Date de publication:
05 2020

Historique:

received: 15 05 2019

revised: 09 12 2019

accepted: 02 01 2020

pubmed: 14 1 2020

medline: 21 10 2020

entrez: 14 1 2020

Statut: ppublish

Résumé

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 Ca We performed whole-exome DNA sequencing 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 (control individuals). In replication studies, we sequenced DNA from patients with early-onset CP (20 years or younger) not associated with alcohol consumption from France (n = 470) and Germany (n = 410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca 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 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3-371.7; P = 2.4 × 10 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 Ca

Sections du résumé

BACKGROUND & AIMS

METHODS

We performed whole-exome DNA sequencing 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 (control individuals). In replication studies, we sequenced DNA from patients with early-onset CP (20 years or younger) not associated with alcohol consumption from France (n = 470) and Germany (n = 410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca

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 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3-371.7; P = 2.4 × 10

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 Ca

Identifiants

DOI: 10.1053/j.gastro.2020.01.005 PMID: 31930989

pubmed: 31930989

pii: S0016-5085(20)30017-2

doi: 10.1053/j.gastro.2020.01.005

pii:

doi:

Substances chimiques

Calcium Channels 0

TRPV Cation Channels 0

TRPV6 protein, human 0

Trpv6 protein, mouse 0

Calcium SY7Q814VUP

Types de publication

Journal Article Multicenter Study Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1626-1641.e8