Department of Internal Medicine I, Martin Luther University, Halle, Germany.
Department of Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany.
Gut. 2018 Oct;67(10):1855-1863. doi: 10.1136/gutjnl-2017-314454. Epub 2017 Jul 28.
Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus.
1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used.
We replicated previously reported risk loci , , and in alcoholic CP patients. We identified (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by . The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk.
An inversion in the locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.
酒精相关性胰腺炎与胃肠道疾病中大量住院治疗相关。尽管其具有重要的临床意义，但酒精性慢性胰腺炎（CP）的遗传易感性尚未得到充分描述。为了确定酒精性 CP 的风险基因，并评估其在非酒精性 CP 中的相关性，我们进行了全基因组关联研究和新胰腺炎基因座的功能特征分析。
1959 年，来自 KORA、LIFE 和 INCIPE 研究的 1959 名欧洲酒精性 CP 患者和基于人群的对照者（n=4708），以及 GESGA 联合会的慢性酗酒者（n=1332），使用 Illumina 技术进行了筛查。为了验证，使用来自相同国家的三个欧洲队列，包括 1650 名非酒精性 CP 患者和 6695 名对照者。
我们在酒精性 CP 患者中复制了先前报道的风险基因座、、和。我们确定了（糜蛋白酶 B1 和 B2）为新的风险基因座，其主要单核苷酸多态性（SNP）为（OR 1.35，95%CI 1.23 至 1.6）。我们发现，位于 基因座的 16.6kb 倒位与 CP 相关的 SNPs 呈连锁不平衡，且与 CP 相关的 SNP 最佳标记为。该关联在三个独立的欧洲非酒精性 CP 队列中得到了验证，该队列包括 1650 名患者和 6695 名对照者（OR 1.62，95%CI 1.42 至 1.86）。该倒位改变了 CTRB1 和 CTRB2 同工型的表达比例，从而影响了保护性胰蛋白酶原的降解，最终影响了胰腺炎的风险。
位于 基因座的倒位改变了酒精性和非酒精性 CP 的风险，表明这些炎症性疾病涉及共同的发病机制。
