Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Hyderabad, India.
Gut. 2013 Nov;62(11):1602-6. doi: 10.1136/gutjnl-2012-302448. Epub 2012 May 12.
In a previous study, the authors have shown that rather than variants in trypsinogen gene(s), mutations in pancreatic secretory trypsin inhibitor (encoded by SPINK1) and cathepsin B (CTSB) are associated with tropical calcific pancreatitis (TCP). Recently, chymotrypsin C (CTRC) variants that diminish its activity or secretion were found to predict susceptibility to chronic pancreatitis (CP). The authors analysed CTRC variants in a large, ethnically matched case-control TCP cohort.
The authors sequenced all eight exons and flanking regions in CTRC in 584 CP patients (497 TCP, 87 idiopathic CP) and 598 normal subjects and analysed the significance of association using χ(2) test. The authors also investigated interaction of CTRC variants with p.N34S SPINK1 and p.L26V CTSB mutations.
The authors identified 14 variants in CTRC, of which non-synonymous variants were detected in 71/584 CP patients (12.2%) and 22/598 controls (3.7%; OR 3.62, 95% CI 2.21 to 5.93; p=6.2 × 10(-8)). Rather than the commonly reported p.K247_R254del variant in Caucasians, p.V235I was the most common mutation in Indian CP patients (28/575 (4.9%); OR 7.60, 95% CI 2.52 to 25.71; p=1.01 × 10(-5)). Another pathogenic variant, p.A73T was identified in 3.1% (18/584) patients compared with 0.3% (2/598) in controls (OR=9.48, 95% CI 2.19 to 41.03, p=2.5 × 10(-4)). The authors also observed significant association for the synonymous variant c.180C>T (p.(=)) with CP (OR 2.71, 95% CI 1.79 to 4.12, p=5.3 × 10(-7)). Two novel nonsense mutations, p.G242AfsX9 and p.W113X were also identified exclusively in CP patients. No interaction between CTRC variants and p.N34S SPINK1 or p.L26V CTSB mutations was observed.
This study on a large cohort of TCP patients provides evidence of allelic heterogeneity and confirms that CTRC variants play a significant role in its pathogenesis.
在之前的研究中，作者已经表明，与胰蛋白酶原基因（s）的变体不同，胰腺分泌的弹性蛋白酶抑制剂（由 SPINK1 编码）和组织蛋白酶 B（CTSB）的突变与热带钙化性胰腺炎（TCP）有关。最近，发现降低糜蛋白酶 C（CTRC）活性或分泌的变体可预测慢性胰腺炎（CP）的易感性。作者在一个大型的、种族匹配的 TCP 病例对照队列中分析了 CTRC 变体。
作者对 497 例 TCP 患者（497 例 TCP，87 例特发性 CP）和 598 例正常对照者的 CTRC 的所有 8 个外显子和侧翼区域进行了测序，并使用卡方检验分析了关联的显著性。作者还研究了 CTRC 变体与 p.N34S SPINK1 和 p.L26V CTSB 突变的相互作用。
作者在 CTRC 中发现了 14 个变体，其中 71/584 例 CP 患者（12.2%）和 22/598 例对照者（3.7%）检测到非同义变体（OR 3.62，95%CI 2.21 至 5.93；p=6.2×10(-8)）。与高加索人中常见的报道的 p.K247_R254del 变体不同，p.V235I 是印度 CP 患者中最常见的突变（28/575（4.9%）；OR 7.60，95%CI 2.52 至 25.71；p=1.01×10(-5)）。与对照组的 0.3%（2/598）相比，另一种致病性变体 p.A73T 在 3.1%（18/584）患者中被发现（OR=9.48，95%CI 2.19 至 41.03，p=2.5×10(-4)）。作者还观察到同义变体 c.180C>T（p.(=))与 CP 显著相关（OR 2.71，95%CI 1.79 至 4.12，p=5.3×10(-7)）。还在 CP 患者中发现了两个新的无意义突变 p.G242AfsX9 和 p.W113X。未观察到 CTRC 变体与 p.N34S SPINK1 或 p.L26V CTSB 突变之间的相互作用。
本研究对一个大型的 TCP 患者队列进行了研究，提供了等位基因异质性的证据，并证实了 CTRC 变体在其发病机制中起着重要作用。
