Characterization of CEL-DUP2: Complete duplication of the carboxyl ester lipase gene is unlikely to influence risk of chronic pancreatitis
Characterization of CEL-DUP2: Complete duplication of the carboxyl ester lipase gene is unlikely to influence risk of chronic pancreatitis
复制标题
DOI：
10.1016/j.pan.2020.01.011
复制
发表时间：
2020-04-01
期刊：
影响因子：
3.6
通讯作者：
Molven, Anders
中科院分区：
文献类型：
--
作者：
Fjeld, Karianne;Masson, Emmanuelle;Molven, Anders
背景与目的：羧酸酯脂肪酶是一种由CEL编码的胰酶，是一种高度多态的人类基因。CEL的致病性变体增加慢性胰腺炎（CP）的风险或导致MODY 8，一种胰腺外分泌和内分泌功能障碍的综合征。方法：采用桑格测序、DNA片段分析、多重连接探针扩增和全基因组测序等方法，对CEL基因的一个新的重复等位基因（CEL-DUP 2）进行结构分析。我们开发了用于筛选CEL-DUP 2的测定，并分析了特发性CP、酒精性CP和胰腺癌的队列。结果：CEL-DUP 2细胞中含有一个完整的CEL基因的额外拷贝。该等位基因可能来自非等位基因同源重组，涉及相邻的CEL假基因。在法国（病例/对照：2.5%/2.4%; P = 1.0）、中国（10.3%/18.1%; P = 0.08）或德国（1.6%/2.3%; P = 0.62）的队列中，我们发现CEL-DUP 2携带者频率与CP之间没有关联。同样，在酒精诱导的胰腺炎（德国：3.2%/2.3%; P = 0.51）或胰腺癌（挪威; 2.5%/3.2%; P = 0.77）中未观察到与疾病的相关性。值得注意的是，中国人CEL-DUP 2的携带频率是欧洲人的三倍多。从CEL-DUP 2载体和controls.Conclusions：我们的研究结果支持的论点，即CEL等位基因的数量不影响胰腺外分泌疾病的风险组织中的CEL蛋白表达是相似的。相反，迄今为止鉴定的致病性CEL变体涉及外显子11序列变化，其实质上改变了蛋白质的尾区。(C)2020年IAP和EPC。Elsevier B. V.出版，保留所有权利。
Background/objectives: Carboxyl ester lipase is a pancreatic enzyme encoded by CEL, an extremely polymorphic human gene. Pathogenic variants of CEL either increases the risk for chronic pancreatitis (CP) or cause MODY8, a syndrome of pancreatic exocrine and endocrine dysfunction. Here, we aimed to characterize a novel duplication allele of CEL (CEL-DUP2) and to investigate whether it associates with CP or pancreatic cancer.Methods: The structure of CEL-DUP2 was determined by a combination of Sanger sequencing, DNA fragment analysis, multiplex ligation-dependent probe amplification and whole-genome sequencing. We developed assays for screening of CEL-DUP2 and analyzed cohorts of idiopathic CP, alcoholic CP and pancreatic cancer. CEL protein expression was analyzed by immunohistochemistry.Results: CEL-DUP2 consists of an extra copy of the complete CEL gene. The allele has probably arisen from non-allelic, homologous recombination involving the adjacent pseudogene of CEL. We found no association between CEL-DUP2 carrier frequency and CP in cohorts from France (cases/controls: 2.5%/2.4%; P = 1.0), China (10.3%18.1%; P = 0.08) or Germany (1.6%/2.3%; P = 0.62). Similarly, no association with disease was observed in alcohol-induced pancreatitis (Germany: 3.2%/2.3%; P = 0.51) or pancreatic cancer (Norway; 2.5%/3.2%; P = 0.77). Notably, the carrier frequency of CEL-DUP2 was more than threefold higher in Chinese compared with Europeans. CEL protein expression was similar in tissues from CEL-DUP2 carriers and controls.Conclusions: Our results support the contention that the number of CEL alleles does not influence the risk of pancreatic exocrine disease. Rather, the pathogenic CEL variants identified so far involve exon 11 sequence changes that substantially alter the protein's tail region. (C) 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.