Transcriptome-wide Mendelian randomization during CD4+ T cell activation reveals immune-related drug targets for cardiometabolic diseases

Xueyan Wu, Hui Ying, Qianqian Yang, Qian Yang, Haoyu Liu, Yilan Ding, Huiling Zhao, Zhihe Chen, Ruizhi Zheng, Hong Lin, Shuangyuan Wang, Mian Li, Tiange Wang, Zhiyun Zhao, Min Xu, Yuhong Chen, Yu Xu, Emma E. Vincent, Maria Carolina Borges, Tom R. Gaunt, Guang Ning, Weiqing Wang (), Yufang Bi (), Jie Zheng () and Jieli Lu ()
Additional contact information
Xueyan Wu: Shanghai Jiao Tong University School of Medicine
Hui Ying: Shanghai Jiao Tong University School of Medicine
Qianqian Yang: Shanghai Jiao Tong University School of Medicine
Qian Yang: University of Bristol
Haoyu Liu: Shanghai Jiao Tong University School of Medicine
Yilan Ding: Shanghai Jiao Tong University School of Medicine
Huiling Zhao: University of Bristol
Zhihe Chen: Shanghai Jiao Tong University School of Medicine
Ruizhi Zheng: Shanghai Jiao Tong University School of Medicine
Hong Lin: Shanghai Jiao Tong University School of Medicine
Shuangyuan Wang: Shanghai Jiao Tong University School of Medicine
Mian Li: Shanghai Jiao Tong University School of Medicine
Tiange Wang: Shanghai Jiao Tong University School of Medicine
Zhiyun Zhao: Shanghai Jiao Tong University School of Medicine
Min Xu: Shanghai Jiao Tong University School of Medicine
Yuhong Chen: Shanghai Jiao Tong University School of Medicine
Yu Xu: Shanghai Jiao Tong University School of Medicine
Emma E. Vincent: University of Bristol
Maria Carolina Borges: University of Bristol
Tom R. Gaunt: University of Bristol
Guang Ning: Shanghai Jiao Tong University School of Medicine
Weiqing Wang: Shanghai Jiao Tong University School of Medicine
Yufang Bi: Shanghai Jiao Tong University School of Medicine
Jie Zheng: Shanghai Jiao Tong University School of Medicine
Jieli Lu: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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+ 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+ 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.

Date: 2024
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DOI: 10.1038/s41467-024-53621-7

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