Masson Emmanuelle, Chen Jian-Min, Scotet Virginie, Le Maréchal Cédric, Férec Claude
Institut National de la Santé et de la Recherche Médicale (INSERM), U613, 29220, Brest, France.
Hum Genet. 2008 Feb;123(1):83-91. doi: 10.1007/s00439-007-0459-3. Epub 2008 Jan 3.
Extensive genetic studies of chronic pancreatitis over the past decade have highlighted the importance of a tightly regulated balance between activation and inactivation of trypsin within the pancreas to disease susceptibility and resistance. The recent identification of chymotrypsin C (CTRC) as enzyme Y, which was proposed to protect the pancreas by degrading prematurely activated trypsinogen within the pancreas 20 years ago, made CTRC an excellent candidate gene for disease-association studies. Here, we analyzed all eight exons of the CTRC gene for conventional genetic variants and copy number variations (CNVs) by direct sequencing and quantitative fluorescent multiplex PCR, respectively, in a total of 287 French white patients (idiopathic x 216; familial x 42; hereditary x 29). While no CNVs were found in any of the 287 subjects, 20 conventional variations including a nonsense mutation (p.W55X), a microdeletion mutation (p.K247_R254del) and nine missense mutations were found in the 216 patients with idiopathic chronic pancreatitis (ICP). Except for two common polymorphisms, all the remaining 18 mutational events represent rare variations, with a minor allele frequency of 0-0.3% in the control population. All these rare variants were always found more frequently in the ICP patients than in the controls, and their combined frequency in the ICP patients (26/216; 12.0%) is significantly different from that in the controls (4/350; 1.1%) (OR = 11.8 [3.9-40.6]), chi (2) = 31.58, P < 10(-6)). This genetic finding, when considered in the perceived role of CTRC in eliminating prematurely activated trypsin, indicated that CTRC is a new pancreatitis susceptibility gene.
过去十年对慢性胰腺炎的广泛遗传学研究突显了胰腺内胰蛋白酶激活与失活之间严格调控的平衡对疾病易感性和抗性的重要性。20年前提出糜蛋白酶C（CTRC）作为酶Y，通过降解胰腺内过早激活的胰蛋白酶原保护胰腺，这使得CTRC成为疾病关联研究的一个极佳候选基因。在此，我们分别通过直接测序和定量荧光多重PCR分析了287名法国白人患者（特发性216例；家族性42例；遗传性29例）CTRC基因的所有八个外显子，以检测常见遗传变异和拷贝数变异（CNV）。虽然在287名受试者中均未发现CNV，但在216例特发性慢性胰腺炎（ICP）患者中发现了20种常见变异，包括一个无义突变（p.W55X）、一个微缺失突变（p.K247_R254del）和九个错义突变。除两个常见多态性外，其余18个突变事件均为罕见变异，在对照人群中的次要等位基因频率为0 - 0.3%。所有这些罕见变异在ICP患者中的出现频率总是高于对照组，其在ICP患者中的合并频率（26/216；12.0%）与对照组（4/350；1.1%）有显著差异（OR = 11.8 [3.9 - 40.6]），χ(2) = 31.58，P < 10(-6)）。考虑到CTRC在消除过早激活的胰蛋白酶中的假定作用，这一遗传学发现表明CTRC是一个新的胰腺炎易感基因。
