Transcriptome-wide Mendelian randomization during CD4+ T cell activation reveals immune-related drug targets for cardiometabolic diseases
Immunity has shown potentials in informing drug development for cardiometabolic diseases, such as type 2 diabetes (T2D) and coronary artery disease (CAD). Here, we performed a transcriptome-wide Mendelian randomization (MR) study to estimate the putative causal effects of 11,021 gene expression profiles during CD4<sup>+</sup> T cells activation on the development of T2D and CAD. Robust MR and colocalization evidence was observed for 162 genes altering T2D risk and 80 genes altering CAD risk, with 12% and 16% respectively demonstrating CD4<sup>+</sup> T cell specificity. We observed temporal causal patterns during T cell activation in 69 gene-T2D pairs and 34 gene-CAD pairs. These genes were eight times more likely to show robust genetic evidence. We further identified 25 genes that were targets for drugs under clinical investigation, including LIPA and GCK. This study provides evidence to support immune-to-metabolic disease connections, and prioritises immune-mediated drug targets for cardiometabolic diseases.
Authors
- Guang Ning
- Jieli Lu (ORCID: https://orcid.org/0000-0003-1317-0896)
- Yufang Bi (ORCID: https://orcid.org/0000-0002-9536-2682)
- Tom R. Gaunt (ORCID: https://orcid.org/0000-0003-0924-3247)
- Xueyan Wu (ORCID: https://orcid.org/0000-0001-9127-7854)
- Zhihe Chen (ORCID: https://orcid.org/0000-0001-8294-6729)
- Ruizhi Zheng (ORCID: https://orcid.org/0000-0002-2068-7597)
- Tiange Wang (ORCID: https://orcid.org/0000-0003-0723-489X)
- Jie Zheng (ORCID: https://orcid.org/0000-0002-6623-6839)
- Qian Yang (ORCID: https://orcid.org/0000-0001-8778-4132)
- Emma E. Vincent (ORCID: https://orcid.org/0000-0002-8917-7384)
- Weiqing Wang (ORCID: https://orcid.org/0000-0001-6027-3084)
- Haoyu Liu
- Yuhong Chen (ORCID: https://orcid.org/0000-0001-6131-7595)
- Mian Li (ORCID: https://orcid.org/0000-0003-1293-3636)
- Min Xu (ORCID: https://orcid.org/0000-0003-3930-8718)
- Hui Ying
- Zhiyun Zhao
- Hong Lin (ORCID: https://orcid.org/0000-0001-5860-4358)
- Qianqian Yang (ORCID: https://orcid.org/0009-0008-0195-833X)
- Huiling Zhao
- Yilan Ding
- Maria Carolina Borges
- Shuangyuan Wang (ORCID: https://orcid.org/0000-0002-1060-492X)
- Yu Xu (ORCID: https://orcid.org/0000-0002-7363-742X)
Institutions
- Shanghai Jiao Tong University (CN)
- Ruijin Hospital (CN)
- University of Bristol (GB)
- NIHR Bristol Biomedical Research Centre (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-28
- DOI
- https://doi.org/10.1038/s41467-024-53621-7
- Citations
- 12
- Primary Topic
- Atherosclerosis and Cardiovascular Diseases
- Type
- article
- Field-Weighted Citation Impact
- 2.89
Funders
- Wellcome Trust
- World Cancer Research Fund International
- NIHR Bristol Biomedical Research Centre
- Cancer Research UK
- National Institute for Health and Care Research
- British Heart Foundation
- Department of Health and Social Care
- Diabetes UK
- University of Bristol
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality
- Shanghai Clinical Research Center
- Medical Research Council
- World Cancer Research Fund
- National Key Research and Development Program of China