Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis
Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis
复制标题
DOI：
10.1038/ng.2007.44
复制
发表时间：
2008-01-01
期刊：
影响因子：
30.8
通讯作者：
Sahin-Toth, Miklos
中科院分区：
文献类型：
--
作者：
Rosendahl, Jonas;Witt, Heiko;Sahin-Toth, Miklos
慢性胰腺炎是胰腺的一种持续性炎症性疾病，其中消化蛋白酶胰蛋白酶具有根本的致病作用。在这里，我们分析了德国特发性或遗传性慢性胰腺炎受试者中编码胰蛋白酶降解酶胰凝乳蛋白酶 C (CTRC) 的基因。该基因的两个改变，p.R254W 和 p.K247_R254del，在胰腺炎组中显着过高，在 901 名受影响个体中存在 30 名 (3.3%)，但在 2,804 名对照中仅存在 21 名 (0.7%)（比值比 (OR)=4.6；置信区间 (CI)=2.6 - 8.0； P=1.3x10(-7))。一项重复研究在 348 名酒精性慢性胰腺炎患者中的 10 名 (2.9%) 中发现了这两种变异，但在 432 名酒精性肝病患者中只有 3 名 (0.7%) (OR=4.2; CI=1.2 - 15.5; P=0.02)。在 71 名患有热带胰腺炎的印度受试者中，有 10 名 (14.1%) 也发现了 CTRC 变异，但在 84 名健康对照者中只有 1 名 (1.2%) (OR=13.6; CI=1.7 - 109.2; P=0.0028)。 CTRC 变体的功能分析显示活性受损和/或分泌减少。结果表明，CTRC 的功能丧失改变会降低其保护性胰蛋白酶降解活性，从而导致胰腺炎。
Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls ( odds ratio (OR)=4.6; confidence interval (CI)=2.6 - 8.0; P=1.3x10(-7)). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 ( 0.7%) subjects with alcoholic liver disease (OR=4.2; CI=1.2 - 15.5; P=0.02). CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR=13.6; CI=1.7 - 109.2; P=0.0028). Functional analysis of the CTRC variants showed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity.