Original ResearchClinical—PancreasVariants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis
Graphical abstract
Section snippets
Study Participants
A 34-year-old man was referred to our hospital for examination of the cause of his CP. He had developed recurrent pancreatitis attacks since the age of 25 years. He had no history of drinking alcohol or smoking. His parents had no past history of pancreatitis.
For the validation study, we enrolled 300 (152 male and 148 female patients; median age at onset, 25 years; range, 1–70 years) Japanese patients with nonalcoholic CP, including 42 patients with family history of recurrent pancreatitis or
Whole-Exome Sequencing Identified p.A210V and De Novo p.D324N Variants in TRPV6
To identify novel pancreatitis susceptibility genes, we performed WES of a patient with idiopathic CP who developed symptoms at the age of 25 years. We identified 10,278 nonsynonymous or splice site variants in this patient. Among them, 421 variants were novel or rare (minor allele frequency, ≤0.01) in 1000 Genomes28 or in the Human Genetic Variation Database.29 After comparison of the data with the WES data of his clinically unaffected parents and visual inspection of the alignment quality
Discussion
Since the landmark discovery of PRSS1 mutations in patients with hereditary pancreatitis,4 the old concept of Hans Chiari that pancreatic inflammation results from autodigestion50 became the predominant pathophysiological model. The identification of mutations in additional susceptibility genes such as SPINK1, CTRC, CPA1, CEL, and PNLIP7, 8, 9, 10, 11 further underlined the enzyme-centered concept of a disturbed balance of pancreatic digestive enzymes and their specific inhibitors within the
Acknowledgments
The authors are grateful to Makiko Sumii, Yoko Tateda, Miyuki Tsuda, Mami Kikuchi, Makiko Nakagawa, and Kiyotaka Kuroda for the excellent technical assistance. The authors also acknowledge the technical support of the Biomedical Research Core of the Tohoku University Graduate School of Medicine.
CRediT Authorship Contributions
Atsushi Masamune, MD, PhD (Conceptualization: Lead; Data curation: Lead; Investigation: Lead; Methodology: Lead; Project administration: Lead; Resources: Lead; Writing – original draft: Lead; Writing –
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Conflicts of interest The authors disclose no conflicts.
Funding This work was supported in part by Grant-in-Aid from the Japan Society for the Promotion of Science (16K15421, 17K15916, 19K17450); Pancreas Research Foundation of Japan; the HIROMI Medical Research Foundation; the Mother and Child Health Foundation; the Smoking Research Foundation, the Ministry of Health, Labour, and Welfare of Japan; Conseil Régional de Bretagne; the Association des Pancréatites Chroniques Héréditaires; the Association de Transfusion Sanguine et de Biogénétique Gaetan Saleun; the Institut National de la Santé et de la Recherche Médicale, France; and the Else Kröner-Fresenius-Stiftung (2017_A108-EKFZ).
Author names in bold designate shared co-first authorship.
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Authors share co-senior authorship.