Investigating the relationship of plasma microRNAs and colorectal cancer risk using genetic evidence
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background:
MicroRNAs (miRNAs) are short, single-stranded RNAs that function as post-transcriptional regulators of gene expression. Although circulating miRNAs have been linked to carcinogenesis, they have not yet been systematically investigated in relation to risk of colorectal cancer (CRC).
Methods:
We used Mendelian randomization (MR) and colocalization analyses to investigate the association of genetically predicted plasma miRNA concentrations (2083 miRNAs in 710 individuals) with risk of CRC (58,221 cases and 67,694 controls). For miRNAs associated with CRC risk, we also investigated their association with circulating plasma proteins (4907 proteins in 35,559 participants), bidirectionally, using MR. We performed pathway enrichment analysis (PEA) to explore downstream molecular pathways.
Results:
Associations of five miRNAs with CRC were found in MR and supported in colocalization analyses. Specifically, miR-146a-5p, miR-21-5p, and miR-4707-3p were positively, and miR-1908-5p and miR-6810-3p were inversely associated with CRC risk. Several protein associations were found for these miRNAs (range of proteins with P < 0.05: 78–796; 211 with FDR < 5%), and 11 pathways were identified in PEA, including regulation of Erb-B2 receptor tyrosine kinase 4 (miR-6810-3p) and insulin-like growth factor pathways (miR-1908-5p).
Conclusions:
Our results support a potential implication of miR-146a-5p, miR-21-5p, miR-4707-3p, miR-1908-5p, and miR-6810-3p to CRC risk. However, their downstream effects should be elucidated before they can be utilized as preventive targets.
MicroRNAs (miRNAs) are short, single-stranded RNAs that function as post-transcriptional regulators of gene expression. Although circulating miRNAs have been linked to carcinogenesis, they have not yet been systematically investigated in relation to risk of colorectal cancer (CRC).
Methods:
We used Mendelian randomization (MR) and colocalization analyses to investigate the association of genetically predicted plasma miRNA concentrations (2083 miRNAs in 710 individuals) with risk of CRC (58,221 cases and 67,694 controls). For miRNAs associated with CRC risk, we also investigated their association with circulating plasma proteins (4907 proteins in 35,559 participants), bidirectionally, using MR. We performed pathway enrichment analysis (PEA) to explore downstream molecular pathways.
Results:
Associations of five miRNAs with CRC were found in MR and supported in colocalization analyses. Specifically, miR-146a-5p, miR-21-5p, and miR-4707-3p were positively, and miR-1908-5p and miR-6810-3p were inversely associated with CRC risk. Several protein associations were found for these miRNAs (range of proteins with P < 0.05: 78–796; 211 with FDR < 5%), and 11 pathways were identified in PEA, including regulation of Erb-B2 receptor tyrosine kinase 4 (miR-6810-3p) and insulin-like growth factor pathways (miR-1908-5p).
Conclusions:
Our results support a potential implication of miR-146a-5p, miR-21-5p, miR-4707-3p, miR-1908-5p, and miR-6810-3p to CRC risk. However, their downstream effects should be elucidated before they can be utilized as preventive targets.
Date Issued
2025-10-02
Date Acceptance
2025-07-31
Citation
BMC Medicine, 2025, 23
ISSN
1741-7015
Publisher
BMC
Journal / Book Title
BMC Medicine
Volume
23
Copyright Statement
© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
10.1186/s12916-025-04311-8
Subjects
MicroRNA
MiRNA
Colorectal cancer
Mendelian randomization
Mechanisms
Proteins
Publication Status
Published
Article Number
ARTN 532