Gene association analysis to determine the causal relationship between immune cells and juvenile idiopathic arthritis

Longhao Chen; Xingchen Zhou; Chao Yang; Hong Jiao Wu; Yu Tian; Shuangwei Hong; Huijie Hu; Kaizheng Wang; Shuang Wu; Zicheng Wei; Tao Li; Yuanshen Huang; Zihan Hua; Qiong Xia; Xiao Jie Chen; Zhizhen Lv; Lijiang Lv

doi:10.1186/s12969-024-00970-8

Gene association analysis to determine the causal relationship between immune cells and juvenile idiopathic arthritis

Pediatr Rheumatol Online J. 2024 Mar 8;22(1):35. doi: 10.1186/s12969-024-00970-8.

Authors

Longhao Chen^#^{1

2

3}, Xingchen Zhou^#^{1

2}, Chao Yang^#¹, Hong Jiao Wu^#⁴, Yu Tian^{1

2}, Shuangwei Hong^{1

2}, Huijie Hu^{1

2}, Kaizheng Wang^{1

2}, Shuang Wu^{1

2}, Zicheng Wei^{1

2}, Tao Li^{1

2}, Yuanshen Huang^{1

2}, Zihan Hua^{1

2}, Qiong Xia^{1

2}, Xiao Jie Chen⁵, Zhizhen Lv^#^{6

7

8}, Lijiang Lv^#^{9

10

11}

Affiliations

¹ The Third Affiliated Hospital of Zhejiang Chinese Medical University (Zhongshan Hospital of Zhejiang Province), Zhejiang, Hangzhou, China.
² The Third School of Clinical Medicine (School of Rehabilitation Medicine), Zhejiang Chinese Medical University, Zhejiang, Hangzhou, China.
³ Research Institute of Tuina (Spinal disease), Zhejiang Chinese Medical University, Zhejiang, Hangzhou, China.
⁴ Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Zhejiang, Hangzhou, China.
⁵ The 72nd Group Army Hospital of Chinese People's Liberation Army, Zhejiang, Huzhou, China.
⁶ The Third Affiliated Hospital of Zhejiang Chinese Medical University (Zhongshan Hospital of Zhejiang Province), Zhejiang, Hangzhou, China. lvzhizhen1992@163.com.
⁷ The Third School of Clinical Medicine (School of Rehabilitation Medicine), Zhejiang Chinese Medical University, Zhejiang, Hangzhou, China. lvzhizhen1992@163.com.
⁸ Research Institute of Tuina (Spinal disease), Zhejiang Chinese Medical University, Zhejiang, Hangzhou, China. lvzhizhen1992@163.com.
⁹ The Third Affiliated Hospital of Zhejiang Chinese Medical University (Zhongshan Hospital of Zhejiang Province), Zhejiang, Hangzhou, China. lvlijiang0288@163.com.
¹⁰ The Third School of Clinical Medicine (School of Rehabilitation Medicine), Zhejiang Chinese Medical University, Zhejiang, Hangzhou, China. lvlijiang0288@163.com.
¹¹ Research Institute of Tuina (Spinal disease), Zhejiang Chinese Medical University, Zhejiang, Hangzhou, China. lvlijiang0288@163.com.

^# Contributed equally.

Abstract

Background: Juvenile idiopathic arthritis (JIA) is a type of chronic childhood arthritis with complex pathogenesis. Immunological studies have shown that JIA is an acquired self-inflammatory disease, involving a variety of immune cells, and it is also affected by genetic and environmental susceptibility. However, the precise causative relationship between the phenotype of immune cells and JIA remains unclear to date. The objective of our study is to approach this inquiry from a genetic perspective, employing a method of genetic association analysis to ascertain the causal relationship between immune phenotypes and the onset of JIA.

Methods: In this study, a two-sample Mendelian randomization (MR) analysis was used to select single nucleotide polymorphisms (SNPs) significantly associated with immune cells as instrumental variables to analyze the bidirectional causal relationship between 731 immune cells and JIA. There were four types of immune features (median fluorescence intensity (MFI), relative cellular (RC), absolute cellular (AC), and morphological parameters (MP)). Finally, the heterogeneity and horizontal reproducibility of the results were verified by sensitivity analysis, which ensured more robust results.

Results: We found that CD3 on CM CD8br was causally associated with JIA at the level of 0.05 significant difference (95% CI = 0.630 ~ 0.847, P = 3.33 × 10^-5, P_FDR = 0.024). At the significance level of 0.20, two immunophenotypes were causally associated with JIA, namely: HLA DR on CD14+ CD16- monocyte (95% CI = 0.633 ~ 0.884, P = 6.83 × 10^-4, P_FDR = 0.16) and HLA DR on CD14+ monocyte (95% CI = 0.627 ~ 0.882, P = 6.9 × 10^-4, P_FDR = 0.16).

Conclusion: Our study assessed the causal effect of immune cells on JIA from a genetic perspective. These findings emphasize the complex and important role of immune cells in the pathogenesis of JIA and lay a foundation for further study of the pathogenesis of JIA.

Keywords: Causation analysis; Gene-wide Association; Immune cell; Juvenile idiopathic arthritis (JIA); Mendelian randomization.

MeSH terms

Arthritis, Juvenile* / genetics
Child
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
HLA-DR Antigens / genetics
Humans
Polymorphism, Single Nucleotide
Reproducibility of Results

Substances

HLA-DR Antigens