Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis
Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis
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DOI：
10.14309/ajg.0000000000000051
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发表时间：
2019-06-01
影响因子：
9.8
通讯作者：
Sahin-Toth, Miklos
中科院分区：
文献类型：
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作者：
Lasher, Denise;Szabo, Andras;Sahin-Toth, Miklos
提示：胰腺实质内消化蛋白酶胰蛋白酶的过早激活是胰腺炎发病机制中的一个关键因素。影响胰内胰蛋白酶活性的基因改变与慢性胰腺炎（CP）有关。最近，羧基酯脂肪酶作为胰蛋白酶非依赖性风险基因出现。在这里，我们评估胰脂肪酶（PNLIP）作为一个潜在的新的易感基因CP。方法：我们分析了所有13个PNLIP外显子在429名非酒精性CP患者和600名对照组来自德国，在632例患者和957名对照组来自法国，在223例患者和1,070名对照组来自日本的DNA测序。此外，我们还分析了来自德国、美国和印度的另外545名CP患者和1，849名对照的选定外显子。我们评估了重组PNLIP变体的细胞分泌、脂肪酶活性和蛋白水解稳定性。结果：在德国发现队列中，8/429（1.9%）患者和2/600（0.3%）对照携带PNLIP错义变体（P = 0.02，比值比[OR] = 5.7，95%置信区间[CI] = 1.1-38.9）。在患者中检测到的变异体易于被胰蛋白酶和胰凝乳蛋白酶蛋白水解降解。在法国重复队列中，早发性CP患者（5/632 [0.8%]）与对照组（1/957 [0.1%]）中蛋白酶敏感变体也富集（P = 0.04，OR = 7.6，95% CI = 0.9-172.9）。相比之下，我们在非欧洲人群中没有检测到蛋白酶敏感的变体。在欧洲的数据中，13/1，163例（1.1%）和3/3，000例对照（0.1%）中发现了蛋白酶敏感性变异（OR = 11.3，95%CI = 3.0-49.9，P < 0.0001）。结论：我们的数据表明，蛋白酶敏感性PNLIP变异是CP发展的新遗传危险因素。
OBJECTIVES:Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intrapancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase emerged as a trypsin-independent risk gene. Here, we evaluated pancreatic lipase (PNLIP) as a potential novel susceptibility gene for CP.METHODS:We analyzed all 13 PNLIP exons in 429 nonalcoholic patients with CP and 600 control subjects from Germany, in 632 patients and 957 controls from France, and in 223 patients and 1,070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 patients with CP and 1,849 controls originating from Germany, United States, and India. We assessed the cellular secretion, lipase activity, and proteolytic stability of recombinant PNLIP variants.RESULTS:In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P = 0.02, odds ratio [OR] = 5.7, 95% confidence interval [CI] = 1.1-38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) vs controls (1/957 [0.1%]) (P = 0.04, OR = 7.6, 95% CI = 0.9-172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1,163 cases (1.1%) and in 3/3,000 controls (0.1%) (OR = 11.3, 95% CI = 3.0-49.9, P < 0.0001).CONCLUSIONS:Our data indicate that protease-sensitive PNLIP variants are novel genetic risk factors for the development of CP.