Variants in the pancreatic CUB and zona pellucida-like domains 1 (CUZD1) gene in early-onset chronic pancreatitis - A possible new susceptibility gene.
Variants in the pancreatic CUB and zona pellucida-like domains 1 (CUZD1) gene in early-onset chronic pancreatitis - A possible new susceptibility gene.
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DOI：
10.1016/j.pan.2022.04.015
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发表时间：
2022-06
期刊：
影响因子：
3.6
通讯作者：
Witt, Heiko
中科院分区：
文献类型：
--
作者：
Rygiel, Agnieszka Magdalena;Unger, Lara Sophie;Sorgel, Franziska Lena;Masson, Emmanuelle;Matsumoto, Ryotaro;Ewers, Maren;Chen, Jian-Min;Bugert, Peter;Buscail, Louis;Gambin, Tomasz;Oracz, Grzegorz;Winiewska-Szajewska, Maria;Mianowska, Agnieszka;Poznanski, Jaroslaw;Kosinska, Joanna;Stawinski, Piotr;Ploski, Rafa;Koziel, Dorota;Gluszek, Stanislaw;Laumen, Helmut;Lindgren, Fredrik;Lohr, J. Matthias;Orekhova, Anna;Rebours, Vinciane;Rosendahl, Jonas;Parniczky, Andrea;Hegyi, Peter;Sasaki, Akira;Kataoka, Fumiya;Tanaka, Yu;Hamada, Shin;Sahin-Toth, Miklos;Hegyi, Eszter;Ferec, Claude;Masamune, Atsushi;Witt, Heiko
非酒精性慢性胰腺炎（NACP）经常发生在与胰腺高表达基因改变相关的遗传易感性环境中。然而，NACP的遗传基础在大量患者中仍未得到解决，需要进一步寻找风险基因。我们分析了CUZD1，它编码CUB和透明带样结构域1蛋白，这些蛋白在胰腺腺泡细胞中含量很高。我们对1163名欧洲患者和2018名欧洲对照进行了编码区测序。此外，我们分析了来自日本的297名患者和1070名对照。我们用Western blotting分析转染细胞中野生型和突变型CUZD1的分泌情况。在欧洲队列中，我们检测到30个非同义变体。使用不同的预测工具（SIFT， CADD, provan, PredictSNP）或这些工具的组合，我们发现了患者中预测的有害变异的积累（p值范围为0.002-0.013；or范围为3.1-5.2）。在日本队列中没有发现关联，其中检测到13个非同义变体。功能研究显示，>使7种变体的分泌减少50%，然而，这些变体在欧洲CP患者中并未显著富集。我们的数据表明CUZD1可能是慢性胰腺炎的一个新的易感基因。这些变异如何导致胰腺炎仍有待阐明。
Non-alcoholic chronic pancreatitis (NACP) frequently develops in the setting of genetic susceptibility associated with alterations in genes that are highly expressed in the pancreas. However, the genetic basis of NACP remains unresolved in a significant number of patients warranting a search for further risk genes. We analyzed CUZD1, which encodes the CUB and zona pellucida-like domains 1 protein that is found in high levels in pancreatic acinar cells. We sequenced the coding region in 1,163 European patients and 2,018 European controls. In addition, we analyzed 297 patients and 1,070 controls from Japan. We analyzed secretion of wild-type and mutant CUZD1 from transfected cells using Western blotting. In the European cohort, we detected 30 non-synonymous variants. Using different prediction tools (SIFT, CADD, PROVEAN, PredictSNP) or the combination of these tools, we found accumulation of predicted deleterious variants in patients (p-value range 0.002–0.013; OR range 3.1–5.2). No association was found in the Japanese cohort, in which 13 non-synonymous variants were detected. Functional studies revealed >50% reduced secretion of 7 variants, however, these variants were not significantly enriched in European CP patients. Our data indicate that CUZD1 might be a novel susceptibility gene for chronic pancreatitis. How these variants predispose to pancreatitis remains to be elucidated.
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