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Published on: September 25, 2011
Comprehensive Mendelian randomization and colocalization analysis of plasma proteomics to identify new therapeutic
Jieming Zuo1, Junhao Chen1, Zhiyong Tan1
1Yunnan Institute of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.
Abstract:
Bladder cancer is characterized by a high recurrence rate and aggressive behavior, with frequent emergence of chemoresistance. Current treatments such as surgery, chemotherapy, and immunotherapy have limited efficacy, underscoring the urgent need for effective early diagnostic biomarkers and novel targeted therapies. Results: In this study, we integrated plasma proteomic data from the UK Biobank Pharma Proteomics Project (UKB-PPP) and the Icelandic deCODE study with genome-wide association study (GWAS) data. We employed two-sample Mendelian randomization (MR), Bayesian colocalization analysis, and SMR/HEIDI tests to systematically identify potential plasma protein targets associated with bladder cancer risk. A total of 199 plasma proteins were found to be significantly associated with bladder cancer risk, among which five proteins (SLURP1, LY6D, WFDC1, NOV, and GSTM3) emerged as core candidate targets. Further validation showed that NOV and GSTM3 demonstrated robust causal associations with bladder cancer across multiple analytical methods, and molecular docking analysis revealed that these two proteins can bind to estrogen/progestin hormone-regulating drugs. Conclusions: Our study identified multiple plasma proteins with causal links to bladder cancer and revealed their potential roles in tumor immune evasion, antioxidant defenses, and tumor metabolism. These findings provide new insights into bladder cancer biology and offer potential targets for precision therapy and drug repositioning.
Insights
This study identifies novel plasma proteins linked to bladder cancer risk, offering potential for early diagnosis and new targeted treatments. Researchers found specific proteins like NOV and GSTM3 may be key to understanding and treating this aggressive cancer.
Area of Science:
- Oncology
- Proteomics
- Genetics
Background:
- Bladder cancer presents high recurrence and chemoresistance, necessitating improved diagnostics and therapies.
- Current treatments show limited efficacy, highlighting the need for novel biomarkers and targeted interventions.
Purpose of the Study:
- To identify plasma protein targets causally associated with bladder cancer risk.
- To explore potential roles of identified proteins in bladder cancer biology and therapeutic strategies.
Main Methods:
- Integration of plasma proteomic data (UKB-PPP, deCODE) with genome-wide association study (GWAS) data.
- Application of two-sample Mendelian randomization (MR), Bayesian colocalization, and SMR/HEIDI analyses.
- Molecular docking to assess drug-binding potential of candidate proteins.
Main Results:
- 199 plasma proteins significantly associated with bladder cancer risk were identified.
- Five core candidate proteins (SLURP1, LY6D, WFDC1, NOV, GSTM3) were highlighted.
- NOV and GSTM3 showed robust causal links to bladder cancer and potential binding to hormone-regulating drugs.
Conclusions:
- Identified plasma proteins have causal links to bladder cancer, implicating roles in immune evasion, antioxidant defense, and metabolism.
- Findings offer new insights into bladder cancer biology.
- Potential targets for precision therapy and drug repositioning were revealed.
