Plasma metabolites and risk of seven cancers: a two-sample Mendelian randomization study among European descendants
Abstract Background While circulating metabolites have been increasingly linked to cancer risk, the causality underlying these associations remains largely uninterrogated. Methods We conducted a comprehensive 2-sample Mendelian randomization (MR) study to evaluate the potential causal relationship b...
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | BMC Medicine |
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| Online Access: | https://doi.org/10.1186/s12916-024-03272-8 |
| _version_ | 1797274356752056320 |
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| author | Yaxin Chen Yufang Xie Hang Ci Zhengpei Cheng Yongjie Kuang Shuqing Li Gang Wang Yawen Qi Jun Tang Dan Liu Weimin Li Yaohua Yang |
| author_facet | Yaxin Chen Yufang Xie Hang Ci Zhengpei Cheng Yongjie Kuang Shuqing Li Gang Wang Yawen Qi Jun Tang Dan Liu Weimin Li Yaohua Yang |
| author_sort | Yaxin Chen |
| collection | DOAJ |
| description | Abstract Background While circulating metabolites have been increasingly linked to cancer risk, the causality underlying these associations remains largely uninterrogated. Methods We conducted a comprehensive 2-sample Mendelian randomization (MR) study to evaluate the potential causal relationship between 913 plasma metabolites and the risk of seven cancers among European-ancestry individuals. Data on variant-metabolite associations were obtained from a genome-wide association study (GWAS) of plasma metabolites among 14,296 subjects. Data on variant-cancer associations were gathered from large-scale GWAS consortia for breast (N = 266,081), colorectal (N = 185,616), lung (N = 85,716), ovarian (N = 63,347), prostate (N = 140,306), renal cell (N = 31,190), and testicular germ cell (N = 28,135) cancers. MR analyses were performed with the inverse variance-weighted (IVW) method as the primary strategy to identify significant associations at Bonferroni-corrected P < 0.05 for each cancer type separately. Significant associations were subjected to additional scrutiny via weighted median MR, Egger regression, MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and reverse MR analyses. Replication analyses were performed using an independent dataset from a plasma metabolite GWAS including 8,129 participants of European ancestry. Results We identified 94 significant associations, suggesting putative causal associations between 66 distinct plasma metabolites and the risk of seven cancers. Remarkably, 68.2% (45) of these metabolites were each associated with the risk of a specific cancer. Among the 66 metabolites, O-methylcatechol sulfate and 4-vinylphenol sulfate demonstrated the most pronounced positive and negative associations with cancer risk, respectively. Genetically proxied plasma levels of these two metabolites were significantly associated with the risk of lung cancer and renal cell cancer, with an odds ratio and 95% confidence interval of 2.81 (2.33–3.37) and 0.49 (0.40–0.61), respectively. None of these 94 associations was biased by weak instruments, horizontal pleiotropy, or reverse causation. Further, 64 of these 94 were eligible for replication analyses, and 54 (84.4%) showed P < 0.05 with association patterns consistent with those shown in primary analyses. Conclusions Our study unveils plausible causal relationships between 66 plasma metabolites and cancer risk, expanding our understanding of the role of circulating metabolites in cancer genetics and etiology. These findings hold promise for enhancing cancer risk assessment and prevention strategies, meriting further exploration. |
| first_indexed | 2024-03-07T14:57:17Z |
| format | Article |
| id | doaj.art-38ae7deb4a1b4f6788cf6c5d63f7f620 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-03-07T14:57:17Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-38ae7deb4a1b4f6788cf6c5d63f7f6202024-03-05T19:21:38ZengBMCBMC Medicine1741-70152024-03-0122111610.1186/s12916-024-03272-8Plasma metabolites and risk of seven cancers: a two-sample Mendelian randomization study among European descendantsYaxin Chen0Yufang Xie1Hang Ci2Zhengpei Cheng3Yongjie Kuang4Shuqing Li5Gang Wang6Yawen Qi7Jun Tang8Dan Liu9Weimin Li10Yaohua Yang11Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan UniversityDepartment of Respiratory and Critical Care Medicine, West China Hospital, Sichuan UniversityInstitute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan UniversityCenter for Public Health Genomics, Department of Public Health Sciences, UVA Comprehensive Cancer Center, School of Medicine, University of VirginiaDepartment of Public Health Sciences, UVA Comprehensive Cancer Center, School of Medicine, University of VirginiaInstitute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan UniversityInnovation Laboratory for Precision Diagnostics, Precision Medicine Research Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan UniversityInstitute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan UniversityInstitute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan UniversityDepartment of Respiratory and Critical Care Medicine, West China Hospital, Sichuan UniversityInstitute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan UniversityCenter for Public Health Genomics, Department of Public Health Sciences, UVA Comprehensive Cancer Center, School of Medicine, University of VirginiaAbstract Background While circulating metabolites have been increasingly linked to cancer risk, the causality underlying these associations remains largely uninterrogated. Methods We conducted a comprehensive 2-sample Mendelian randomization (MR) study to evaluate the potential causal relationship between 913 plasma metabolites and the risk of seven cancers among European-ancestry individuals. Data on variant-metabolite associations were obtained from a genome-wide association study (GWAS) of plasma metabolites among 14,296 subjects. Data on variant-cancer associations were gathered from large-scale GWAS consortia for breast (N = 266,081), colorectal (N = 185,616), lung (N = 85,716), ovarian (N = 63,347), prostate (N = 140,306), renal cell (N = 31,190), and testicular germ cell (N = 28,135) cancers. MR analyses were performed with the inverse variance-weighted (IVW) method as the primary strategy to identify significant associations at Bonferroni-corrected P < 0.05 for each cancer type separately. Significant associations were subjected to additional scrutiny via weighted median MR, Egger regression, MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and reverse MR analyses. Replication analyses were performed using an independent dataset from a plasma metabolite GWAS including 8,129 participants of European ancestry. Results We identified 94 significant associations, suggesting putative causal associations between 66 distinct plasma metabolites and the risk of seven cancers. Remarkably, 68.2% (45) of these metabolites were each associated with the risk of a specific cancer. Among the 66 metabolites, O-methylcatechol sulfate and 4-vinylphenol sulfate demonstrated the most pronounced positive and negative associations with cancer risk, respectively. Genetically proxied plasma levels of these two metabolites were significantly associated with the risk of lung cancer and renal cell cancer, with an odds ratio and 95% confidence interval of 2.81 (2.33–3.37) and 0.49 (0.40–0.61), respectively. None of these 94 associations was biased by weak instruments, horizontal pleiotropy, or reverse causation. Further, 64 of these 94 were eligible for replication analyses, and 54 (84.4%) showed P < 0.05 with association patterns consistent with those shown in primary analyses. Conclusions Our study unveils plausible causal relationships between 66 plasma metabolites and cancer risk, expanding our understanding of the role of circulating metabolites in cancer genetics and etiology. These findings hold promise for enhancing cancer risk assessment and prevention strategies, meriting further exploration.https://doi.org/10.1186/s12916-024-03272-8Plasma metabolitesCancer riskMendelian randomization |
| spellingShingle | Yaxin Chen Yufang Xie Hang Ci Zhengpei Cheng Yongjie Kuang Shuqing Li Gang Wang Yawen Qi Jun Tang Dan Liu Weimin Li Yaohua Yang Plasma metabolites and risk of seven cancers: a two-sample Mendelian randomization study among European descendants BMC Medicine Plasma metabolites Cancer risk Mendelian randomization |
| title | Plasma metabolites and risk of seven cancers: a two-sample Mendelian randomization study among European descendants |
| title_full | Plasma metabolites and risk of seven cancers: a two-sample Mendelian randomization study among European descendants |
| title_fullStr | Plasma metabolites and risk of seven cancers: a two-sample Mendelian randomization study among European descendants |
| title_full_unstemmed | Plasma metabolites and risk of seven cancers: a two-sample Mendelian randomization study among European descendants |
| title_short | Plasma metabolites and risk of seven cancers: a two-sample Mendelian randomization study among European descendants |
| title_sort | plasma metabolites and risk of seven cancers a two sample mendelian randomization study among european descendants |
| topic | Plasma metabolites Cancer risk Mendelian randomization |
| url | https://doi.org/10.1186/s12916-024-03272-8 |
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