Transcriptome-wide Mendelian randomization exploring dynamic CD4+ T cell gene expression in colorectal cancer development

Recent research suggests higher circulating lymphocyte counts may protect against colorectal cancer (CRC). However, the role of specific lymphocyte subtypes and activation states remain unclear. CD4+ T cells-a highly dynamic lymphocyte subtype-undergo gene expression changes upon activation that are critical to their effector function. Previous studies using bulk tissue have limited our understanding of their role in CRC risk to static associations. We applied Mendelian randomization (MR) and genetic colocalisation to evaluate causal relationships of gene expression on CRC risk across multiple CD4+ T cell subtypes and activation states. Genetic proxies were obtained from single-cell transcriptomic data, allowing us to investigate the causal effect of expression of 1,805 genes across CD4+ T cell activation states on CRC risk (78,473 cases; 107,143 controls). Analyses were stratified by CRC anatomical subsites and sex, with sensitivity analyses assessing whether the observed effect estimates were likely to be CD4+ T cell-specific. We identified 6 genes-FADS2, FHL3, HLA-DRB1, HLA-DRB5, RPL28, and TMEM258-with strong evidence for a causal role in CRC development (FDR-P < 0.05; colocalisation H4 > 0.8). Causal estimates varied by CD4+ T cell subtype, activation state, CRC subsite and sex. However, many of genetic proxies used to instrument gene expression in CD4+ T cells also act as eQTLs in other tissues, highlighting the challenges of using genetic proxies to instrument tissue-specific expression changes. We demonstrate the importance of capturing the dynamic nature of CD4+ T cells in understanding CRC risk, and prioritize genes for further investigation in cancer prevention.

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Publication Details

Journal
Journal of Leukocyte Biology
Published
2025-09-15
DOI
https://doi.org/10.1093/jleuko/qiaf131
Citations
1
Primary Topic
Colorectal Cancer Treatments and Studies
Type
article
Field-Weighted Citation Impact
1.05
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article

Transcriptome-wide Mendelian randomization exploring dynamic CD4+ T cell gene expression in colorectal cancer development

Gareth W. Jones, James Yarmolinsky, Andrea Gsur, Amanda I. Phipps et al.
1 citations
Journal of Leukocyte Biology
Colorectal Cancer Treatments and Studies
1.05
article

Transcriptome-wide Mendelian randomization exploring dynamic CD4+ T cell gene expression in colorectal cancer development

Gareth W. Jones, James Yarmolinsky, Andrea Gsur, Amanda I. Phipps, Annika Lindblom, Matthew A. Lee, Claire Elizabeth Thomas, Veronika Vymetálková, Jeroen R. Huyghe, Ulrike Peters, Xueyan Wu, Rish K. Pai, Daniel D. Buchanan, Lucy J. Goudswaard, Anna H. Wu, Marc J. Gunter, Shuji Ogino, Emma E. Vincent, Emma Hazelwood, Alicja Wolk, Robert C. Grant, Jie Zheng, Benedita Deslandes
article en
1 citations

Abstract

Recent research suggests higher circulating lymphocyte counts may protect against colorectal cancer (CRC). However, the role of specific lymphocyte subtypes and activation states remain unclear. CD4+ T cells-a highly dynamic lymphocyte subtype-undergo gene expression changes upon activation that are critical to their effector function. Previous studies using bulk tissue have limited our understanding of their role in CRC risk to static associations. We applied Mendelian randomization (MR) and genetic colocalisation to evaluate causal relationships of gene expression on CRC risk across multiple CD4+ T cell subtypes and activation states. Genetic proxies were obtained from single-cell transcriptomic data, allowing us to investigate the causal effect of expression of 1,805 genes across CD4+ T cell activation states on CRC risk (78,473 cases; 107,143 controls). Analyses were stratified by CRC anatomical subsites and sex, with sensitivity analyses assessing whether the observed effect estimates were likely to be CD4+ T cell-specific. We identified 6 genes-FADS2, FHL3, HLA-DRB1, HLA-DRB5, RPL28, and TMEM258-with strong evidence for a causal role in CRC development (FDR-P < 0.05; colocalisation H4 > 0.8). Causal estimates varied by CD4+ T cell subtype, activation state, CRC subsite and sex. However, many of genetic proxies used to instrument gene expression in CD4+ T cells also act as eQTLs in other tissues, highlighting the challenges of using genetic proxies to instrument tissue-specific expression changes. We demonstrate the importance of capturing the dynamic nature of CD4+ T cells in understanding CRC risk, and prioritize genes for further investigation in cancer prevention.

Journal of Leukocyte BiologyVol. 117(10)
Seattle Pacific University (US), University of Southern California (US), Brigham and Women's Hospital (US), The Royal Melbourne Hospital (AU), Karolinska University Hospital (SE), Harvard University (US), The University of Melbourne (AU), University of Washington (US), Czech Academy of Sciences (CZ), Ruijin Hospital (CN), Princess Margaret Cancer Centre (CA), Karolinska Institutet (SE), University of Bristol (GB), Fred Hutch Cancer Center (US), Comprehensive Cancer Center Vienna (AT), Victorian Comprehensive Cancer Centre (AU), Dana-Farber Cancer Institute (US), Mayo Clinic in Arizona (US), Czech Academy of Sciences, Institute of Experimental Medicine (CZ), MRC Epidemiology Unit (GB), Centre international de recherche sur le cancer (FR), Imperial College London (GB), Medical University of Vienna (AT)
Openalex Percentile: Top 18%
Colorectal Cancer Treatments and Studies
1.05
DOIOpen Access PDFOpenAlex
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