How do immune cells shape type 1 diabetes? Insights from Mendelian randomization

Yunfeng Yu; Xinyu Yang; Juan Deng; Jingyi Wu; Siyang Bai; Rong Yu

doi:10.3389/fendo.2024.1402956

How do immune cells shape type 1 diabetes? Insights from Mendelian randomization

Front Endocrinol (Lausanne). 2024 Dec 24:15:1402956. doi: 10.3389/fendo.2024.1402956. eCollection 2024.

Authors

Yunfeng Yu^#^{1

2}, Xinyu Yang^#¹, Juan Deng^#², Jingyi Wu³, Siyang Bai¹, Rong Yu^{1

2}

Affiliations

¹ School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China.
² Department of Endocrinology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China.
³ The Third School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.

^# Contributed equally.

Abstract

Objective: The role of immune cells in type 1 diabetes (T1D) is unclear. The aim of this study was to assess the causal effect of different immune cells on T1D using Mendelian randomization (MR).

Methods: A dataset of immune cell phenotypes (numbered from GCST0001391 to GCST0002121) was obtained from the European Bioinformatics Institute, while a T1D dataset (numbered finngen_R10_T1D) was obtained from FinnGen. Single nucleotide polymorphisms meeting the conditions were screened stepwise according to the assumptions of association, independence, and exclusivity. Inverse variance weighted was used as the main method for the MR analysis. MR-Egger was used to assess the horizontal pleiotropy of the results. Cochran's Q and the leave-one-out method were respectively used for the heterogeneity analysis and the sensitivity analysis of the results.

Results: MR analysis showed that effector memory (EM) double-negative (DN) (CD4^-CD8^-) %T cells [odds ratio (OR) = 1.157, 95% confidence interval (95% CI) = 1.016-1.318, p = 0.028, false discovery rate (FDR) = 0.899], EM CD8^br %T cells (OR = 1.049, 95% CI = 1.003-1.098, p = 0.037, FDR = 0.902), CD28 on CD28⁺CD45RA⁺CD8^br (OR = 1.334, 95% CI = 1.132-1.571, p = 0.001, FDR = 0.044), IgD⁺CD38^dim %lymphocytes (OR = 1.045, 95% CI = 1.002-1.089, p = 0.039, FDR = 0.902), CD80 on monocytes (OR = 1.084, 95% CI = 1.013-1.161, p = 0.020, FDR = 0.834), SSC-A on plasmacytoid dendritic cells (pDCs) (OR = 1.174, 95% CI = 1.004-1.372, p = 0.044, FDR = 0.902), and FSC-A on pDCs (OR = 1.182, 95% CI = 1.011-1.382, p = 0.036, FDR = 0.902) were associated with an increased genetic susceptibility to T1D. Cochran's Q showed that there was heterogeneity for CD28 on the CD28⁺CD45RA⁺CD8^br results (p = 0.043), whereas there was no heterogeneity for the other results (p ≥ 0.05). The sensitivity analysis showed that the MR analysis results were robust.

Conclusion: The MR analysis demonstrated that seven immune cell phenotypes were associated with an increased genetic susceptibility to T1D. These findings provide a new direction for the pathogenesis of and the drug development for T1D.

Keywords: GWAS; Mendelian randomization; immune cell; phenotype; type 1 diabetes.

MeSH terms

Dendritic Cells / immunology
Diabetes Mellitus, Type 1* / genetics
Diabetes Mellitus, Type 1* / immunology
Diabetes Mellitus, Type 1* / pathology
Genetic Predisposition to Disease
Humans
Mendelian Randomization Analysis*
Polymorphism, Single Nucleotide*

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by The Key Support Project of the Regional Innovation and Development Joint Fund of the National Natural Science Foundation of China (U21A20411).