Genetically predicted gut bacteria, circulating bacteria-associated metabolites and pancreatic ductal adenocarcinoma: a Mendelian randomisation study
Abstract Pancreatic ductal adenocarcinoma (PDAC) has high mortality and rising incidence rates. Recent data indicate that the gut microbiome and associated metabolites may play a role in the development of PDAC. To complement and inform observational studies, we investigated associations of genetica...
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Nature Portfolio
2024-10-01
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| author | Neil Daniel Riccardo Farinella Anastasia Chrysovalantou Chatziioannou Mazda Jenab Ana-Lucia Mayén Cosmeri Rizzato Flavia Belluomini Federico Canzian Arianna Tavanti Pekka Keski-Rahkonen David J. Hughes Daniele Campa |
| author_facet | Neil Daniel Riccardo Farinella Anastasia Chrysovalantou Chatziioannou Mazda Jenab Ana-Lucia Mayén Cosmeri Rizzato Flavia Belluomini Federico Canzian Arianna Tavanti Pekka Keski-Rahkonen David J. Hughes Daniele Campa |
| author_sort | Neil Daniel |
| collection | DOAJ |
| description | Abstract Pancreatic ductal adenocarcinoma (PDAC) has high mortality and rising incidence rates. Recent data indicate that the gut microbiome and associated metabolites may play a role in the development of PDAC. To complement and inform observational studies, we investigated associations of genetically predicted abundances of individual gut bacteria and genetically predicted circulating concentrations of microbiome-associated metabolites with PDAC using Mendelian randomisation (MR). Gut microbiome-associated metabolites were identified through a comprehensive search of Pubmed, Exposome Explorer and Human Metabolome Database. Single Nucleotide Polymorphisms (SNPs) associated by Genome-Wide Association Studies (GWAS) with circulating levels of 109 of these metabolites were collated from Pubmed and the GWAS catalogue. SNPs for 119 taxonomically defined gut genera were selected from a meta-analysis performed by the MiBioGen consortium. Two-sample MR was conducted using GWAS summary statistics from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including a total of 8,769 cases and 7,055 controls. Inverse variance-weighted MR analyses were performed along with sensitivity analyses to assess potential violations of MR assumptions. Nominally significant associations were noted for genetically predicted circulating concentrations of mannitol (odds ratio per standard deviation [ORSD] = 0.97; 95% confidence interval [CI]: 0.95–0.99, p = 0.006), methionine (ORSD= 0.97; 95%CI: 0.94-1.00, p = 0.031), stearic acid (ORSD= 0.93; 95%CI: 0.87–0.99, p = 0.027), carnitine = (ORSD=1.01; 95% CI: 1.00-1.03, p = 0.027), hippuric acid (ORSD= 1.02; 95%CI: 1.00-1.04, p = 0.038) and 3-methylhistidine (ORSD= 1.05; 95%CI: 1.01–1.10, p = 0.02). Two gut microbiome genera were associated with reduced PDAC risk; Clostridium sensu stricto 1 (OR: 0.88; 95%CI: 0.78–0.99, p = 0.027) and Romboutsia (OR: 0.87; 95%CI: 0.80–0.96, p = 0.004). These results, though based only on genetically predicted gut microbiome characteristics and circulating bacteria-related metabolite concentrations, provide evidence for causal associations with pancreatic carcinogenesis. |
| format | Article |
| id | doaj-art-da2d98f474ff4bada2734a28ec4ef6e1 |
| institution | Kabale University |
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| language | English |
| publishDate | 2024-10-01 |
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| spelling | doaj-art-da2d98f474ff4bada2734a28ec4ef6e12024-12-22T12:25:58ZengNature PortfolioScientific Reports2045-23222024-10-0114111210.1038/s41598-024-77431-5Genetically predicted gut bacteria, circulating bacteria-associated metabolites and pancreatic ductal adenocarcinoma: a Mendelian randomisation studyNeil Daniel0Riccardo Farinella1Anastasia Chrysovalantou Chatziioannou2Mazda Jenab3Ana-Lucia Mayén4Cosmeri Rizzato5Flavia Belluomini6Federico Canzian7Arianna Tavanti8Pekka Keski-Rahkonen9David J. Hughes10Daniele Campa11Molecular Epidemiology of Cancer Group, UCD Conway Institute, School of Biomedical and Biomolecular Sciences, University College DublinDepartment of Biology, University of PisaNutrition and Metabolism Branch, International Agency for Research on Cancer (IARC)Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC)Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC)Department of Biology, University of PisaDepartment of Biology, University of PisaGenomic Epidemiology Group, German Cancer Research Center (DKFZ)Department of Biology, University of PisaNutrition and Metabolism Branch, International Agency for Research on Cancer (IARC)Molecular Epidemiology of Cancer Group, UCD Conway Institute, School of Biomedical and Biomolecular Sciences, University College DublinDepartment of Biology, University of PisaAbstract Pancreatic ductal adenocarcinoma (PDAC) has high mortality and rising incidence rates. Recent data indicate that the gut microbiome and associated metabolites may play a role in the development of PDAC. To complement and inform observational studies, we investigated associations of genetically predicted abundances of individual gut bacteria and genetically predicted circulating concentrations of microbiome-associated metabolites with PDAC using Mendelian randomisation (MR). Gut microbiome-associated metabolites were identified through a comprehensive search of Pubmed, Exposome Explorer and Human Metabolome Database. Single Nucleotide Polymorphisms (SNPs) associated by Genome-Wide Association Studies (GWAS) with circulating levels of 109 of these metabolites were collated from Pubmed and the GWAS catalogue. SNPs for 119 taxonomically defined gut genera were selected from a meta-analysis performed by the MiBioGen consortium. Two-sample MR was conducted using GWAS summary statistics from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including a total of 8,769 cases and 7,055 controls. Inverse variance-weighted MR analyses were performed along with sensitivity analyses to assess potential violations of MR assumptions. Nominally significant associations were noted for genetically predicted circulating concentrations of mannitol (odds ratio per standard deviation [ORSD] = 0.97; 95% confidence interval [CI]: 0.95–0.99, p = 0.006), methionine (ORSD= 0.97; 95%CI: 0.94-1.00, p = 0.031), stearic acid (ORSD= 0.93; 95%CI: 0.87–0.99, p = 0.027), carnitine = (ORSD=1.01; 95% CI: 1.00-1.03, p = 0.027), hippuric acid (ORSD= 1.02; 95%CI: 1.00-1.04, p = 0.038) and 3-methylhistidine (ORSD= 1.05; 95%CI: 1.01–1.10, p = 0.02). Two gut microbiome genera were associated with reduced PDAC risk; Clostridium sensu stricto 1 (OR: 0.88; 95%CI: 0.78–0.99, p = 0.027) and Romboutsia (OR: 0.87; 95%CI: 0.80–0.96, p = 0.004). These results, though based only on genetically predicted gut microbiome characteristics and circulating bacteria-related metabolite concentrations, provide evidence for causal associations with pancreatic carcinogenesis.https://doi.org/10.1038/s41598-024-77431-5Mendelian randomisationGut microbiomeBacteria-related metabolitesPancreatic ductal adenocarcinoma |
| spellingShingle | Neil Daniel Riccardo Farinella Anastasia Chrysovalantou Chatziioannou Mazda Jenab Ana-Lucia Mayén Cosmeri Rizzato Flavia Belluomini Federico Canzian Arianna Tavanti Pekka Keski-Rahkonen David J. Hughes Daniele Campa Genetically predicted gut bacteria, circulating bacteria-associated metabolites and pancreatic ductal adenocarcinoma: a Mendelian randomisation study Scientific Reports Mendelian randomisation Gut microbiome Bacteria-related metabolites Pancreatic ductal adenocarcinoma |
| title | Genetically predicted gut bacteria, circulating bacteria-associated metabolites and pancreatic ductal adenocarcinoma: a Mendelian randomisation study |
| title_full | Genetically predicted gut bacteria, circulating bacteria-associated metabolites and pancreatic ductal adenocarcinoma: a Mendelian randomisation study |
| title_fullStr | Genetically predicted gut bacteria, circulating bacteria-associated metabolites and pancreatic ductal adenocarcinoma: a Mendelian randomisation study |
| title_full_unstemmed | Genetically predicted gut bacteria, circulating bacteria-associated metabolites and pancreatic ductal adenocarcinoma: a Mendelian randomisation study |
| title_short | Genetically predicted gut bacteria, circulating bacteria-associated metabolites and pancreatic ductal adenocarcinoma: a Mendelian randomisation study |
| title_sort | genetically predicted gut bacteria circulating bacteria associated metabolites and pancreatic ductal adenocarcinoma a mendelian randomisation study |
| topic | Mendelian randomisation Gut microbiome Bacteria-related metabolites Pancreatic ductal adenocarcinoma |
| url | https://doi.org/10.1038/s41598-024-77431-5 |
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