胰腺癌中的转录组整个关联研究和孟德尔随机化确定了与2型糖尿病和静脉血栓栓塞的敏感性基因和因果关系
Transcriptome-wide association study and Mendelian randomization in pancreatic cancer identifies susceptibility genes and causal relationships with type 2 diabetes and venous thromboembolism
影响因子:10.80000
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
摘要
关于胰腺腺癌（PDAC）遗传学的两个重要问题是1。生殖线遗传变异会影响该癌症的发生率。 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和FBXL20）和十个先前报道的基因（INHBA，SMC2，ABO，PDX1，MTMR6，ACOT2，PGAP3，PGAP3，Stard3，stard3，GSDMB，GSDMB，ADAM33）。 MR提供了使用HNF4G和PDX1基因座中的遗传仪器对PDAC对T2D的因果关系的支持，VTE对涉及ABO基因座的PDAC的单向因果关系（OR 2.12，P <1E-7）。没有发现PDAC对VTE的因果作用的证据。这些分析确定了PDAC的候选敏感性基因和疾病关系，需要进一步研究。 HNF4G和PDX1可能诱导PDAC相关的糖尿病，而ABO可能会诱导VTE对PDAC的致病作用。
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).