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Transcriptome-wide Mendelian randomization exploring dynamic CD4+ T cell gene expression in colorectal cancer
Benedita Deslandes1,2, Xueyan Wu3,4, Matthew A Lee5
1MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom.
Journal of Leukocyte Biology
|September 20, 2025
Summary
Higher CD4+ T cell gene expression may causally influence colorectal cancer (CRC) risk. This study identifies six genes potentially impacting CRC development, highlighting the dynamic role of these immune cells in cancer prevention.
Area of Science:
- Immunology
- Genetics
- Cancer Research
Background:
- Circulating lymphocyte counts are linked to colorectal cancer (CRC) protection, but specific roles of lymphocyte subtypes and activation states are unclear.
- CD4+ T cells, crucial for immune response, exhibit dynamic gene expression changes upon activation, impacting their function.
- Previous bulk tissue studies offer limited insight into the dynamic role of CD4+ T cells in CRC risk.
Purpose of the Study:
- To investigate the causal relationships between gene expression in various CD4+ T cell subtypes and activation states and CRC risk.
- To identify specific genes with a causal role in CRC development by analyzing gene expression data from CD4+ T cells.
- To explore the influence of CD4+ T cell dynamics on CRC risk across different anatomical subsites and sexes.
Main Methods:
- Applied Mendelian randomization (MR) and genetic colocalization analyses.
- Utilized genetic proxies from single-cell transcriptomic data for 1,805 genes across CD4+ T cell activation states.
- Analyzed a large dataset of 78,473 CRC cases and 107,143 controls, with stratification by CRC subsite and sex.
Main Results:
- Identified six genes (FADS2, FHL3, HLA-DRB1, HLA-DRB5, RPL28, TMEM258) with significant evidence for a causal role in CRC development (FDR-P < 0.05; colocalization H4 > 0.8).
- Observed variations in causal estimates based on CD4+ T cell subtype, activation state, CRC subsite, and sex.
- Noted that genetic proxies for CD4+ T cell expression also function as eQTLs in other tissues, indicating challenges in assessing tissue-specific effects.
Conclusions:
- Capturing the dynamic nature of CD4+ T cells is crucial for understanding CRC risk.
- Prioritized six genes for further investigation in the context of cancer prevention strategies.
- Emphasized the complexity of using genetic proxies for tissue-specific gene expression analysis in immune cells.
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