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

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Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis.
Gastroenterology ( IF 25.7 ) Pub Date : 2020-01-10 , DOI: 10.1053/j.gastro.2020.01.005
Atsushi Masamune ₁ , Hiroshi Kotani ₂ , Franziska Lena Sörgel ₃ , Jian-Min Chen ₄ , Shin Hamada ₁ , Reiko Sakaguchi ₅ , Emmanuelle Masson ₆ , Eriko Nakano ₁ , Yoichi Kakuta ₁ , Tetsuya Niihori ₇ , Ryo Funayama ₈ , Matsuyuki Shirota ₈ , Tatsuya Hirano ₂ , Tetsuya Kawamoto ₂ , Atsuki Hosokoshi ₂ , Kiyoshi Kume ₁ , Lara Unger ₃ , Maren Ewers ₃ , Helmut Laumen ₃ , Peter Bugert ₉ , Masayuki X Mori ₂ , Volodymyr Tsvilovskyy ₁₀ , Petra Weißgerber ₁₁ , Ulrich Kriebs ₁₀ , Claudia Fecher-Trost ₁₁ , Marc Freichel ₁₀ , Kalliope N Diakopoulos ₁₂ , Alexandra Berninger ₁₂ , Marina Lesina ₁₂ , Kentaro Ishii ₁₃ , Takao Itoi ₁₃ , Tsukasa Ikeura ₁₄ , Kazuichi Okazaki ₁₄ , Tom Kaune ₁₅ , Jonas Rosendahl ₁₅ , Masao Nagasaki ₁₆ , Yasuhito Uezono ₁₇ , Hana Algül ₁₂ , Keiko Nakayama ₈ , Yoichi Matsubara ₁₈ , Yoko Aoki ₇ , Claude Férec ₆ , Yasuo Mori ₂ , Heiko Witt ₃ , Tooru Shimosegawa ₁

Affiliation

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan.
Else Kröner-Fresenius-Zentrum für Ernährungsmedizin, Paediatric Nutritional Medicine, Technische Universität München, Freising, Germany.
Inserm, Univ Brest, EFS, UMR 1078, GGB, Brest, France.
Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan.
Inserm, Univ Brest, EFS, UMR 1078, GGB, Brest, France; CHU Brest, Service de Génétique, Brest, France.
Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Japan.
Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg-Hessen, Mannheim, Germany.
Pharmakologisches Institut, Universität Heidelberg, Heidelberg, Germany; German Center for Cardiovascular Research, partner site Heidelberg, Germany.
Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, Germany.
Mildred Scheel Chair of Tumor Metabolism and Comprehensive Cancer Center Munich at the Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan.
Department of Gastroenterology and Hepatology, Kansai Medical University, Hirakata, Japan.
Department of Internal Medicine I, Martin Luther University, Halle (Saale), Germany.
Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
Cancer Pathophysiology Division, National Cancer Center Research Institute, Tokyo, Japan.
National Center for Child Health and Development, Tokyo, Japan.

BACKGROUND & AIMS 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 Ca2+-selective ion channel, in an international cohort of patients and in mice. 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 Ca2+ imaging assays. CP was induced by repeated injections of cerulein in TRPV6mut/mut mice. 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 × 10-8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P = 6.2 × 10-8). Variants that did not affect the function of the TRPV6 product (p.I223T and p.D324N) were overrepresented in Japanese patients vs control individuals (OR, 10.9; 95% CI, 4.5-25.9; P = 7.4 × 10-9 for p.I223T and P = .01 for p.D324N), whereas the p.L299Q was overrepresented in European patients vs control individuals (OR, 3.0; 95% CI, 1.9-4.8; P = 1.2 × 10-5). TRPV6mut/mut mice given cerulein developed more severe pancreatitis than control mice, as shown by increased levels of pancreatic enzymes, histologic alterations, and pancreatic fibrosis. 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 Ca2+ balance in pancreatic cells. TRPV6 regulates Ca2+ homeostasis and pancreatic inflammation.

中文翻译：

影响钙通道TRPV6功能的变异与早期发作的慢性胰腺炎相关。

背景与目的胰腺钙水平的变化会影响分泌，并可能参与慢性胰腺炎（CP）的发展。我们在国际队列的患者和小鼠中研究了CP与瞬时受体电位阳离子通道亚家族V成员6基因（TRPV6）的关联，该基因编码Ca2 +-选择性离子通道。方法我们对患有特发性CP的患者及其没有CP的父母进行了全外显子组DNA测序。我们通过对300位CP患者（与饮酒无关）和1070位日本普通人群（对照组）的DNA进行测序，验证了我们的发现。在复制研究中，我们对来自法国（n = 470）和德国（n = 410）饮酒无关的早发性CP（20岁或更年轻）患者的DNA进行了测序。我们在HEK293细胞中表达了TRPV6变体，并使用Ca2 +成像测定法测量了它们的活性。通过在TRPV6mut / mut小鼠中反复注射青霉素来诱导CP。结果我们在索引患者中确定了TRPV6中的c.629C> T（p.A210V）和c.970G> A（p.D324N）变体。在日本的300名患者中有13名（4.3％）和1070名对照个体中有1名（0.1％）发现了影响TRPV6产品功能的变异体（优势比[OR]为48.4； 95％置信区间[CI]为6.3- 371.7； P = 2.4×10-8）。124例早发性CP患者中有12例（9.7％）具有此类变异。在来自欧洲的复制集中，有18位CP患者（2。与0个对照个体相比（0％）携带影响TRPV6产品功能的变异体（P = 6.2×10-8）。不影响TRPV6产物功能的变体（p.I223T和p.D324N）在日本患者与对照组中的比例过高（OR，10.9; 95％CI，4.5-25.9; P = 7.4×10-9 p.D324N的I223T和P = 0.01），而欧洲患者与对照组相比p.L299Q的比例过高（OR，3.0； 95％CI，1.9-4.8； P = 1.2×10-5）。胰酶水平升高，组织学改变和胰腺纤维化表明，给予了铜绿蛋白的TRPV6mut / mut小鼠比对照组小鼠更严重的胰腺炎。结论我们发现与酒精消费无关的早发性CP患者携带TRPV6变异体，影响其功能，可能是通过改变胰腺细胞中的Ca2 +平衡来实现的。TRPV6调节Ca2 +稳态和胰腺炎症。

更新日期：2020-01-10

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