关于胰腺腺癌 (PDAC) 遗传学的两个重要问题是 1. 哪些种系遗传变异影响这种癌症的发病率； 2. PDAC 是否会导致相关非恶性表型，例如 2 型糖尿病 (T2D) 和静脉血栓栓塞 (VTE)。在这项针对 8803 名 PDAC 患者和 67,523 名对照者的研究中，我们首先进行了大规模转录组研究广泛关联研究旨在调查正常胰腺组织中遗传决定的基因表达与 PDAC 风险之间的关联。其次，我们使用孟德尔随机化（MR）分析PDAC、T2D（74,124例病例和824,006名对照）和VTE（30,234例病例和172,122名对照）之间的因果关系。16个基因显示与PDAC风险相关（FDR <0.10），包括尚未报告 PDAC 风险的 6 个基因（PPIP5K2、TFR2、HNF4G、LRRC10B、PRC1 和 FBXL20）和先前报告的 10 个基因（INHBA、SMC2、ABO、PDX1、MTMR6、ACOT2、PGAP3、STARD3、GSDMB、ADAM33）。 MR 使用 HNF4G 和 PDX1 基因座中的遗传仪器支持 PDAC 对 T2D 的因果影响，以及涉及 ABO 基因座的 VTE 对 PDAC 的单向因果关系（OR 2.12，P < 1e-7）。没有发现 PDAC 对 VTE 因果影响的证据。这些分析确定了 PDAC 的候选易感基因和疾病关系，值得进一步研究。 HNF4G 和 PDX1 可能诱发 PDAC 相关糖尿病，而 ABO 可能诱发 VTE 对 PDAC 的致病作用。美国国立卫生研究院。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Two important questions regarding the genetics of pancreatic adenocarcinoma (PDAC) are 1. Which germline genetic variants influence the incidence of this cancer; and 2. Whether PDAC causally predisposes to associated non-malignant phenotypes, such as type 2 diabetes (T2D) and venous thromboembolism (VTE).In this study of 8803 patients with PDAC and 67,523 controls, we first performed a large-scale transcriptome-wide association study to investigate the association between genetically determined gene expression in normal pancreas tissue and PDAC risk. Secondly, we used Mendelian Randomization (MR) to analyse the causal relationships among PDAC, T2D (74,124 cases and 824,006 controls) and VTE (30,234 cases and 172,122 controls).Sixteen genes showed an association with PDAC risk (FDR <0.10), including six genes not yet reported for PDAC risk (PPIP5K2, TFR2, HNF4G, LRRC10B, PRC1 and FBXL20) and ten previously reported genes (INHBA, SMC2, ABO, PDX1, MTMR6, ACOT2, PGAP3, STARD3, GSDMB, ADAM33). MR provided support for a causal effect of PDAC on T2D using genetic instruments in the HNF4G and PDX1 loci, and unidirectional causality of VTE on PDAC involving the ABO locus (OR 2.12, P < 1e-7). No evidence of a causal effect of PDAC on VTE was found.These analyses identified candidate susceptibility genes and disease relationships for PDAC that warrant further investigation. HNF4G and PDX1 may induce PDAC-associated diabetes, whereas ABO may induce the causative effect of VTE on PDAC.National Institutes of Health (USA).Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.