Gastroenterology:影响钙通道TRPV6功能的变异与早期发作的慢性胰腺炎相关

2020-05-04 MedSci原创 MedSci原创

钙水平的变化会影响胰腺的分泌,并可能参与慢性胰腺炎(CP)的发生发展。本项研究在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。

背景与目标: 钙水平的变化会影响胰腺的分泌,并可能参与慢性胰腺炎(CP)的发生发展。本项研究在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:研究人员对患有特发性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。在复制研究中,研究人员对与法国(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。同时在HEK293细胞中表达了TRPV6变体,并使用Ca 2+成像测定法测量了它们的活性。通过在TRPV6 mut / mut小鼠中反复注射铜蓝蛋白诱导CP 的产生。

结果: 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。在欧洲的复制集中,与0个对照个体相比,有18个CP(2.0%)患者携带影响TRPV6产品功能的变异体(P = 6.2×10 –8)。在日本患者与对照组相比,不影响TRPV6功能的变体(p.I223T和p.D324N)的比例过高(OR,10.9; 95%CI,4.5–25.9;P = 7.4× 10–9,p .I223T和p = D324N的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)。胰酶水平升高的TRPV6 mut / mut小鼠比对照组小鼠更严重的胰腺炎,表现为胰腺酶水平升高,组织学改变和胰腺纤维化。

结论: 我们发现与不饮酒无关的早发性CP患者携带TRPV6变异体,可能通过改变胰腺细胞中Ca 2+平衡来影响其产物的功能。TRPV6会调节Ca 2+稳态和胰腺炎症。

原始出处:

Atsushi Masamune. Et al. Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis. Gastroenterology. 2020.

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