Transcriptome-wide Mendelian randomization exploring dynamic CD4+ T cell gene expression in colorectal cancer development
Status Publisher Jazyk angličtina Země Velká Británie, Anglie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
40974097
DOI
10.1093/jleuko/qiaf131
PII: 8257067
Knihovny.cz E-zdroje
- Klíčová slova
- CD4+ T cells, Mendelian randomization, colorectal cancer, gene expression, genetic epidemiology,
- Publikační typ
- časopisecké články MeSH
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 six 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.
Center for Cancer Research Medical University of Vienna Vienna Austria
Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden
Department of Epidemiology and Biostatistics School of Public Health Imperial College London UK
Department of Epidemiology Harvard T H Chan School of Public Health Boston Massachusetts USA
Department of Epidemiology University of Washington Seattle Washington USA
Department of Laboratory Medicine and Pathology Mayo Clinic Arizona Scottsdale AZ USA
Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden
Department of Oncologic Pathology Dana Farber Cancer Institute Boston Massachusetts USA
Division of Medical Oncology and Hematology Princess Margaret Cancer Centre Toronto Canada
Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden
MRC Integrative Epidemiology Unit University of Bristol Bristol UK
Nutrition and Metabolism Branch International Agency for Research on Cancer WHO Lyon France
Population Health Sciences Bristol Medical School University of Bristol Bristol UK
Public Health Sciences Division Fred Hutchinson Cancer Center Seattle Washington USA
School of Cellular and Molecular Medicine University of Bristol Bristol UK
Translational Health Sciences Bristol Medical School University of Bristol Bristol UK
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