AI Article Synopsis
- This study investigates the genetic factors influencing pancreatic adenocarcinoma (PDAC) risk and its relationship with type 2 diabetes (T2D) and venous thromboembolism (VTE).
- It analyzed data from 8,803 PDAC patients and 67,523 controls, using genetic analysis to identify 16 associated genes, including six novel ones.
- Findings suggest that specific genes (HNF4G and PDX1) may link PDAC to T2D, while ABO may indicate a causal relationship of VTE affecting PDAC, calling for more research on these genetic influences.
Article Abstract
Background: 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).
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).
Findings: 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). No evidence of a causal effect of PDAC on VTE was found.
Interpretation: 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.
Funding: National Institutes of Health (USA).
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284564 | PMC |
| http://dx.doi.org/10.1016/j.ebiom.2024.105233 | DOI Listing |
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