胰腺癌的转录组全基因关联研究与孟德尔随机分析：识别易感基因及其与2型糖尿病和静脉血栓栓塞的因果关系

Transcriptome-wide association study and Mendelian randomization in pancreatic cancer identifies susceptibility genes and causal relationships with type 2 diabetes and venous thromboembolism

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EBioMedicine

影响因子:10.8

分区:医学1区 Top / 医学：研究与实验1区

发表日期:2024 Aug

作者: Marcus C B Tan, Chelsea A Isom, Yangzi Liu, David-Alexandre Trégouët, , Lang Wu, Dan Zhou, Eric R Gamazon

DOI: 10.1016/j.ebiom.2024.105233

摘要

关于胰腺导管腺癌（PDAC）遗传学的两个重要问题是：1. 哪些种系遗传变异影响该癌的发生；2. PDAC是否因果性地促进相关的非恶性表型，如2型糖尿病（T2D）和静脉血栓栓塞（VTE）。本研究包括8803名PDAC患者和67,523名对照，首先进行了大规模的转录组全基因关联分析，调查正常胰腺组织中遗传决定的基因表达与PDAC风险的关系。其次，利用孟德尔随机（MR）分析PDAC、T2D（74,124例病例和824,006对照）与VTE（30,234例病例和172,122对照之间的因果关系。研究发现16个基因与PDAC风险相关（FDR<0.10），其中包括尚未报道的6个基因（PPIP5K2、TFR2、HNF4G、LRRC10B、PRC1和FBXL20）以及10个已报道的基因（INHBA、SMC2、ABO、PDX1、MTMR6、ACOT2、PGAP3、STARD3、GSDMB和ADAM33）。MR分析支持HNF4G和PDX1基因座的遗传工具显示PDAC对T2D具有因果作用，且ABO基因座涉及VTE对PDAC的单向因果关系（比值比2.12，P<1×10^-7）。未发现PDAC对VTE的因果关系。这些分析识别了PDAC的潜在易感基因和疾病关系，值得进一步研究。HNF4G和PDX1可能引发与PDAC相关的糖尿病，ABO可能引起VTE对PDAC的因果作用。美国国家卫生研究院。

Abstract

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).