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. 2025 Jun 4;22(1):24.
doi: 10.1186/s12014-025-09545-5.

Associations of plasma protein levels with risk of colorectal cancer: a proteome-wide Mendelian randomization study

Zhen-Kun Pan  1 , Meng-Hua Wu  2 , Hua Shi  1 , Yong-Jian Ni  1 , Quan-Li Geng  1 , Jin-Sheng Ye  3
Affiliations

Associations of plasma protein levels with risk of colorectal cancer: a proteome-wide Mendelian randomization study

Zhen-Kun Pan et al. Clin Proteomics. .

Abstract

Background: The treatment of advanced or metastatic colorectal cancer (CRC) poses a global challenge. Mendelian Randomization (MR) has been primarily applied for repurposing licensed drugs and uncovering new therapeutic targets.

Objective: This study aims to systematically identify potential plasma protein targets for CRC using proteome-wide Mendelian randomization and evaluate their potential side effects through phenome-wide association studies (Phe-WAS).

Methods: We conducted a comprehensive proteome-wide MR study to assess the causal relationships between plasma proteins and the risk of CRC and evaluate their potential side effects through Phe-WAS. The plasma proteins were sourced from the Finland and Iceland decode database, encompassing GWAS data for plasma proteins (Olink-619 samples across 2925 proteins, SomaScan -828 samples across 7596 proteins and Iceland decode database across 4907 proteins). Additionally, GWAS data for CRC were extracted from the UK Biobank-SAIGE database, including 3051 cases and 382,756 controls. Subsequently, colocalization analysis was performed to identify shared causal variants between plasma proteins and CRC. Finally, a phenome-wide association study (Phe-WAS) was conducted to examine the potential adverse effects of druggable proteins for CRC, utilizing the extensive UK Biobank-SAIGE database, encompassing 783 phenotypes.

Results: The MR analysis identified GREM1, DKKL1, and CHRDL2 as plasma proteins whose genetically predicted levels were positively associated with CRC risk, whereas TMEM132A was inversely associated with CRC risk (P_fdr < 0.05). The colocalization analysis identified these four proteins as shared variation with CRC (PPH3 + PPH4 > 0.7), suggesting that these proteins represent potential direct targets for CRC intervention. Further phenotype-wide association studies showed no significant potential side effects of these targets (P_fdr > 0.05).

Conclusion: This proteome-wide Mendelian randomization study offers a comprehensive molecular landscape of CRC, identifying GREM1, DKKL1, CHRDL2, and TMEM132A as potential therapeutic targets. Our research provides a critical foundation for future experimental validation and therapeutic development in colorectal cancer management.

Keywords: Colorectal cancer; Drug target; Mendelian randomization; Phenome-wide association study; Plasma proteins.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare no competing interests. Ethics approval: This study exclusively utilized publicly available, anonymized genetic summary data from large-scale genomic databases. No individual-level patient data were accessed or processed. Key Ethical Considerations: All source databases obtained appropriate ethical approvals, Data were aggregated and anonymized prior to analysis, No direct human or animal experimentation was conducted, No additional institutional review board (IRB) approval was required, Informed consent for data collection was obtained by the original data repositories. This study adheres to the principles of the Declaration of Helsinki and follows international guidelines for genetic data research. Human and animal rights: No animals/humans were used for studies that are the basis of this research. Consent for publication: Not applicable.

Figures

Fig. 1
Fig. 1
Flowchart of the study design
Fig. 2
Fig. 2
Forest plot of the MR results: Effects of 4 plasma proteins on CRC. CI: confidence interval; OR: odds ratio
Fig. 3
Fig. 3
Volcano plot of MR results: Causal relationship between plasma proteins and CRC
Fig. 4
Fig. 4
Manhattan plot of result of Phe-WAS analysis of associations between 4 CRC-associated plasma proteins and other disease outcomes
See this image and copyright information in PMC

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