Metformin and the risk of malignant tumors of digestive system: a mendelian randomization study
Abstract Background Observational studies suggest that metformin may reduce the risk of malignant tumors of the digestive system (MTDS), but these findings are often confounded by bias and unmeasured variables. Recent meta-analyses have questioned these associations, emphasizing the need for robust...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | Diabetology & Metabolic Syndrome |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13098-024-01573-9 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841544431377842176 |
|---|---|
| author | Ping Liu Junqi Xiao Jinghuang Xiao Jumei Zhou |
| author_facet | Ping Liu Junqi Xiao Jinghuang Xiao Jumei Zhou |
| author_sort | Ping Liu |
| collection | DOAJ |
| description | Abstract Background Observational studies suggest that metformin may reduce the risk of malignant tumors of the digestive system (MTDS), but these findings are often confounded by bias and unmeasured variables. Recent meta-analyses have questioned these associations, emphasizing the need for robust causal inference. Methods Mendelian randomization (MR) was used to evaluate the causal relationship between metformin and MTDS. Genetic variants associated with metformin’s molecular targets were selected from GTEx, eQTLGen, and UK Biobank and validated using genetic colocalization to ensure instrument validity. GWAS summary statistics for MTDS, encompassing up to 314,193 controls and 6,847 colorectal cancer cases, were obtained from FinnGen and EBI. The primary analysis employed the inverse-variance weighted (IVW) method, supplemented by MR-Egger, weighted median, and weighted mode analyses. Bonferroni correction was applied to adjust for multiple testing across 14 cancer types. Results Genetically proxied metformin use was associated with an increased risk of colorectal cancer (OR = 2.38, 95%CI = 1.38–4.09, P = 0.0018) and related subtypes. No causal relationship was found for hepatocellular carcinoma, gastric cancer, pancreatic cancer, or other digestive system cancers. The robustness of these findings was supported by sensitivity analyses, which indicated no significant pleiotropy, and leave-one-out tests. Conclusion This study provides robust genetic evidence that metformin use increases the risk of colorectal cancer, challenging its role as a preventive agent for digestive cancers. These findings emphasize the need for clinicians to carefully evaluate the risks and benefits of metformin, particularly in populations at higher risk for colorectal cancer. Future research should focus on delineating the mechanisms underlying this association to optimize the use of metformin in clinical practice. |
| format | Article |
| id | doaj-art-568b8d35784e4eb69869c587c844700d |
| institution | Kabale University |
| issn | 1758-5996 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Diabetology & Metabolic Syndrome |
| spelling | doaj-art-568b8d35784e4eb69869c587c844700d2025-01-12T12:33:32ZengBMCDiabetology & Metabolic Syndrome1758-59962025-01-0117111010.1186/s13098-024-01573-9Metformin and the risk of malignant tumors of digestive system: a mendelian randomization studyPing Liu0Junqi Xiao1Jinghuang Xiao2Jumei Zhou3Department of Radiation Oncology and Hunan Key Laboratory of Translational Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, HunanCancer HospitalCancer center, The Second Affiliated Hospital, Hengyang Medical School, University of South ChinaDepartment of Radiation Oncology and Hunan Key Laboratory of Translational Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, HunanCancer HospitalDepartment of Radiation Oncology and Hunan Key Laboratory of Translational Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, HunanCancer HospitalAbstract Background Observational studies suggest that metformin may reduce the risk of malignant tumors of the digestive system (MTDS), but these findings are often confounded by bias and unmeasured variables. Recent meta-analyses have questioned these associations, emphasizing the need for robust causal inference. Methods Mendelian randomization (MR) was used to evaluate the causal relationship between metformin and MTDS. Genetic variants associated with metformin’s molecular targets were selected from GTEx, eQTLGen, and UK Biobank and validated using genetic colocalization to ensure instrument validity. GWAS summary statistics for MTDS, encompassing up to 314,193 controls and 6,847 colorectal cancer cases, were obtained from FinnGen and EBI. The primary analysis employed the inverse-variance weighted (IVW) method, supplemented by MR-Egger, weighted median, and weighted mode analyses. Bonferroni correction was applied to adjust for multiple testing across 14 cancer types. Results Genetically proxied metformin use was associated with an increased risk of colorectal cancer (OR = 2.38, 95%CI = 1.38–4.09, P = 0.0018) and related subtypes. No causal relationship was found for hepatocellular carcinoma, gastric cancer, pancreatic cancer, or other digestive system cancers. The robustness of these findings was supported by sensitivity analyses, which indicated no significant pleiotropy, and leave-one-out tests. Conclusion This study provides robust genetic evidence that metformin use increases the risk of colorectal cancer, challenging its role as a preventive agent for digestive cancers. These findings emphasize the need for clinicians to carefully evaluate the risks and benefits of metformin, particularly in populations at higher risk for colorectal cancer. Future research should focus on delineating the mechanisms underlying this association to optimize the use of metformin in clinical practice.https://doi.org/10.1186/s13098-024-01573-9MetforminMalignant tumorsMendelian randomization |
| spellingShingle | Ping Liu Junqi Xiao Jinghuang Xiao Jumei Zhou Metformin and the risk of malignant tumors of digestive system: a mendelian randomization study Diabetology & Metabolic Syndrome Metformin Malignant tumors Mendelian randomization |
| title | Metformin and the risk of malignant tumors of digestive system: a mendelian randomization study |
| title_full | Metformin and the risk of malignant tumors of digestive system: a mendelian randomization study |
| title_fullStr | Metformin and the risk of malignant tumors of digestive system: a mendelian randomization study |
| title_full_unstemmed | Metformin and the risk of malignant tumors of digestive system: a mendelian randomization study |
| title_short | Metformin and the risk of malignant tumors of digestive system: a mendelian randomization study |
| title_sort | metformin and the risk of malignant tumors of digestive system a mendelian randomization study |
| topic | Metformin Malignant tumors Mendelian randomization |
| url | https://doi.org/10.1186/s13098-024-01573-9 |
| work_keys_str_mv | AT pingliu metforminandtheriskofmalignanttumorsofdigestivesystemamendelianrandomizationstudy AT junqixiao metforminandtheriskofmalignanttumorsofdigestivesystemamendelianrandomizationstudy AT jinghuangxiao metforminandtheriskofmalignanttumorsofdigestivesystemamendelianrandomizationstudy AT jumeizhou metforminandtheriskofmalignanttumorsofdigestivesystemamendelianrandomizationstudy |