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Transcriptome-wide association study and Mendelian randomization in pancreatic cancer identifies susceptibility genes and causal relationships with type 2 diabetes and venous thromboembolism.
Tuesday,2024-09-17 13:29 America/Los_Angeles — ecterry
| Title | Transcriptome-wide association study and Mendelian randomization in pancreatic cancer identifies susceptibility genes and causal relationships with type 2 diabetes and venous thromboembolism. |
| Publication Type | Journal Article |
| Year of Publication | 2024 |
| Authors | Tan, MCB, Isom, CA, Liu, Y, Trégouët, D-A, Wu, L, Zhou, D, Gamazon, ER |
| Corporate/Institutional Authors | INVENT Consortium |
| Journal | EBioMedicine |
| Volume | 106 |
| Pagination | 105233 |
| Date Published | 2024 Aug |
| ISSN | 2352-3964 |
| Keywords | Diabetes Mellitus, Type 2, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Pancreatic Neoplasms, Polymorphism, Single Nucleotide, Transcriptome, Venous Thromboembolism |
| Abstract | <p><b>BACKGROUND: </b>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).</p><p><b>METHODS: </b>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).</p><p><b>FINDINGS: </b>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.</p><p><b>INTERPRETATION: </b>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.</p><p><b>FUNDING: </b>National Institutes of Health (USA).</p> |
| DOI | 10.1016/j.ebiom.2024.105233 |
| Alternate Journal | EBioMedicine |
| PubMed ID | 39002386 |
| PubMed Central ID | PMC11284564 |
| Grant List | R01 GM140287 / GM / NIGMS NIH HHS / United States R01 HG011138 / HG / NHGRI NIH HHS / United States U24 OD035523 / OD / NIH HHS / United States R56 AG068026 / AG / NIA NIH HHS / United States R35 HG010718 / HG / NHGRI NIH HHS / United States |
ePub date:
24/08