Pediatric Nutritional Medicine & Else Kröner-Fresenius-Centre for Nutritional Medicine (EKFZ), Technical University Munich (TUM), Freising, Germany.
Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, MA, 02118, United States; Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, United States.
Pancreatology. 2022 Sep;22(6):713-718. doi: 10.1016/j.pan.2022.06.258. Epub 2022 Jun 23.
Genetic alterations in digestive enzymes have been associated with chronic pancreatitis (CP). Recently, chymotrypsin like elastase 3B (CELA3B) emerged as a novel risk gene. Thus, we evaluated CELA3B in two European cohorts with CP.
We analyzed all 8 CELA3B exons in 550 German non-alcoholic CP (NACP) patients and in 241 German controls by targeted DNA sequencing. In addition, we analyzed exons 6 and 7 by Sanger sequencing and the c.129+1G>A variant by melting curve analysis in 1078 further German controls. As replication cohort, we investigated up to 243 non-German European NACP patients and up to 1665 controls originating from Poland, Hungary, and Sweden. We assessed the cellular secretion and the elastase activity of recombinant CELA3B variants.
In the German discovery cohort, we detected a splice-site variant in intron 2, c.129+1G>A, in 9/550 (1.64%) CP patients and in 5/1319 (0.38%) controls (P=0.007, OR=4.4, 95% CI=1.5-13.0). In the European replication cohort, this variant was also enriched in patients (9/178 [5.06%]) versus controls (13/1247 [1.04%]) (P=0.001, OR=5.1, 95% CI=2.1-12.0). We did not find the two previously reported codon 90 variants, p.R90C and p.R90L.
Our data indicate that CELA3B is a susceptibility gene for CP. In contrast to previous reports suggesting that increased CELA3B activity is associated with CP risk, the splice-site variant identified here is predicted to cause diminished CELA3B expression. How reduced CELA3B function predisposes to pancreatitis remains to be elucidated.
消化酶的基因改变与慢性胰腺炎（CP）有关。最近，糜蛋白酶样弹性蛋白酶 3B（CELA3B）作为一种新的风险基因出现。因此，我们在两个欧洲队列中评估了 CELA3B 在 CP 中的作用。
我们通过靶向 DNA 测序分析了 550 名德国非酒精性 CP（NACP）患者和 241 名德国对照者的 8 个 CELA3B 外显子。此外，我们通过 Sanger 测序分析了外显子 6 和 7，并通过熔解曲线分析分析了 1078 名德国对照者中的 c.129+1G>A 变体。作为复制队列，我们研究了来自波兰、匈牙利和瑞典的最多 243 名非德国欧洲 NACP 患者和最多 1665 名对照者。我们评估了重组 CELA3B 变体的细胞分泌和弹性酶活性。
在德国发现队列中，我们在 9/550（1.64%）CP 患者和 5/1319（0.38%）对照者中检测到内含子 2 的剪接位点变异，c.129+1G>A（P=0.007，OR=4.4，95%CI=1.5-13.0）。在欧洲复制队列中，该变体在患者（9/178 [5.06%]）中也比对照者（13/1247 [1.04%]）更为丰富（P=0.001，OR=5.1，95%CI=2.1-12.0）。我们没有发现以前报道的两个密码子 90 变异，即 p.R90C 和 p.R90L。
我们的数据表明 CELA3B 是 CP 的易感基因。与以前的报告表明增加 CELA3B 活性与 CP 风险相关相反，这里鉴定的剪接位点变异预计会导致 CELA3B 表达减少。减少的 CELA3B 功能如何导致胰腺炎仍有待阐明。
