METHODS: 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).
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: National Institutes of Health (USA).
方法:在这项研究中,8803例PDAC患者和67,523例对照,我们首先进行了大规模的全转录组关联研究,以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)来分析PDAC之间的因果关系,T2D(74,124例和824,006例对照)和VTE(30,234例和172,122例对照)。
结果:16个基因显示与PDAC风险相关(FDR<0.10),包括六个尚未报告的PDAC风险基因(PPIP5K2,TFR2,HNF4G,LRRC10B,PRC1和FBXL20)和10个先前报道的基因(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为PDAC对T2D的因果效应提供了支持,以及涉及ABO基因座的PDAC上VTE的单向因果关系(OR2.12,P<1e-7)。没有发现PDAC对VTE有因果关系的证据。
结论: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相关的糖尿病,而ABO可能诱导VTE对PDAC的致病作用。
背景:美国国立卫生研究院。