Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.
Eur J Gastroenterol Hepatol. 2009 Aug;21(8):889-94. doi: 10.1097/MEG.0b013e32832183cf.
Tropical calcific pancreatitis (TCP) is a relatively common form of chronic pancreatitis in parts of Asia and Africa. The SPINK1 variant p.N34S is strongly associated with TCP, but other genetic factors remain to be defined. Chymotrypsinogen C (CTRC) degrades trypsinogen and loss-of-function variants have been found in European patients with chronic pancreatitis. Preliminary data indicate that CTRC might increase the risk for TCP.
We selected 150 Indian TCP patients and 150 Indian controls to perform mutational screening of the complete coding region of CTRC and exon 3 of SPINK1. We performed in-silico analysis and functional studies of novel CTRC variants.
We identified eight variants among this sample. Three were synonymous and c.180 C>T was significantly enriched in patients (odds ratio=2.09; 95% confidence interval=1.19-3.67; P=0.03). We identified a novel nonsynonymous CTRC (p.G61R) variant in one of 146 patients (0.7%), but absent from controls. In-silico analysis showed that this variant affected a conserved residue, and functional analysis showed that p.G61R results in a complete loss of CTRC secretion from transiently transfected human embryonic kidney 293T cells. SPINK1 p.N34S was present in 31.8% of patients compared with 4.7% in controls, there was no significant cosegregation with CTRC variants.
The contribution of CTRC variants to TCP is relatively small, but the identification of novel loss-of-function variants (p.G61R) underscores the importance of the trypsinogen pathway in causing TCP.
热带钙化性胰腺炎（TCP）是亚洲和非洲部分地区一种较为常见的慢性胰腺炎。丝氨酸蛋白酶抑制剂 Kazal 型 1（SPINK1）变异 p.N34S 与 TCP 强烈相关，但其他遗传因素仍有待确定。糜蛋白酶原 C（CTRC）可降解胰蛋白酶原，欧洲慢性胰腺炎患者中已发现其功能丧失变异。初步数据表明，CTRC 可能会增加 TCP 的风险。
我们选择了 150 名印度 TCP 患者和 150 名印度对照者，对 CTRC 完整编码区和 SPINK1 外显子 3 进行了突变筛查。我们对新发现的 CTRC 变异进行了计算机分析和功能研究。
在该样本中发现了 8 个变异。其中 3 个为同义突变，c.180 C>T 在患者中明显富集（比值比=2.09；95%置信区间=1.19-3.67；P=0.03）。我们在 146 名患者中的 1 名（0.7%）中发现了一种新的非同义 CTRC（p.G61R）变异，但在对照中不存在。计算机分析显示该变异影响了一个保守残基，功能分析显示 p.G61R 导致瞬时转染的人胚肾 293T 细胞中 CTRC 完全丧失分泌。与对照组的 4.7%相比，SPINK1 p.N34S 在患者中的出现率为 31.8%，与 CTRC 变异无明显共分离。
CTRC 变异对 TCP 的贡献相对较小，但新型功能丧失变异（p.G61R）的鉴定突出了胰蛋白酶原途径在导致 TCP 中的重要性。
