From the Ariel Precision Medicine.
Pancreas. 2020 Aug;49(7):983-998. doi: 10.1097/MPA.0000000000001612.
Chronic pancreatitis is the end stage of a pathologic inflammatory syndrome with multiple etiological factors, including genetic. We hypothesized that some pancreatitis etiology originates in pancreatic acinar or duct cells and requires both injury and compensatory mechanism failure.
One hundred pancreatitis patients were assessed using a DNA sequencing panel for pancreatitis. Cooccurrence of variants within and between genes was measured. Gene coexpression was confirmed via published single-cell RNA sequencing.
One hundred and twenty-one variants were identified in 2 or more patients, 15 of which were enriched compared with reference populations. Single cell RNA-sequencing data verified coexpression of GGT1, CFTR, and PRSS1 in duct cells, PRSS1, CPA1, CEL, CTRC, and SPINK1 in acinar cells, and UBR1 in both. Multiple-risk variants with injury/stress effects (CEL, CFTR, CPA1, PRSS1) and impaired cell protection (CTRC, GGT1, SPINK1, UBR1) cooccur within duct cells, acinar cells, or both.
Pancreatitis is a complex disorder with genetic interactions across genes and cell types. These findings suggest a new, non-Mendelian genetic risk/etiology paradigm where a combination of nonpathogenic genetic risk variants in groups of susceptibility genes and injury/dysfunction response genes contribute to acquired pancreatic disease.
慢性胰腺炎是一种具有多种病因的病理炎症综合征的终末期，包括遗传因素。我们假设一些胰腺炎的病因起源于胰腺腺泡或导管细胞，需要损伤和代偿机制同时失效。
使用胰腺炎 DNA 测序panel 对 100 例胰腺炎患者进行评估。测量基因内和基因间变异的共现情况。通过已发表的单细胞 RNA 测序来验证基因共表达。
在 2 个或更多患者中发现了 121 个变异，其中 15 个与参考人群相比存在富集。单细胞 RNA-seq 数据验证了 GGT1、CFTR 和 PRSS1 在导管细胞中的共表达，PRSS1、CPA1、CEL、CTRC 和 SPINK1 在腺泡细胞中的共表达，以及 UBR1 在两者中的共表达。具有损伤/应激作用的多风险变异（CEL、CFTR、CPA1、PRSS1）和受损细胞保护作用的变异（CTRC、GGT1、SPINK1、UBR1）在导管细胞、腺泡细胞或两者中共同出现。
胰腺炎是一种具有基因间相互作用的复杂疾病，涉及多个基因和细胞类型。这些发现表明了一种新的、非孟德尔遗传风险/病因学范式，即一组易感基因和损伤/功能障碍反应基因中的非致病性遗传风险变异的组合，导致获得性胰腺疾病。
