Association of TIM-3 with anterior uveitis and associated systemic immune diseases: a Mendelian randomization analysis

Dan Lin; Rong-Cheng Zhu; Chun Tang; Fen-Fen Li; Mei-Ling Gao; Yu-Qin Wang

doi:10.3389/fmed.2023.1183326

Association of TIM-3 with anterior uveitis and associated systemic immune diseases: a Mendelian randomization analysis

Front Med (Lausanne). 2023 Jun 15:10:1183326. doi: 10.3389/fmed.2023.1183326. eCollection 2023.

Authors

Dan Lin^#^{1

2}, Rong-Cheng Zhu^#³, Chun Tang^{1

2}, Fen-Fen Li^{1

2}, Mei-Ling Gao², Yu-Qin Wang^{1

2}

Affiliations

¹ National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China.
² State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China.
³ The Second School of Medicine, Wenzhou Medical University, Wenzhou, China.

^# Contributed equally.

Abstract

Background: We aimed to investigate the causal association between TIM-3, an immune checkpoint inhibitor, and anterior uveitis (AU), as well as associated systemic immune diseases.

Materials and methods: We performed two-sample Mendelian randomization (MR) analyses to estimate the causal effects of TIM-3 on AU and three associated systemic diseases, namely ankylosing spondylitis (AS), Crohn's disease (CD), and ulcerative colitis (UC). Single-nucleotide polymorphisms (SNPs) associated with AU, AS, CD, and UC were selected as the outcomes: AU GWAS with 2,752 patients with acute AU accompanied with AS (cases) and 3,836 AS patients (controls), AS GWAS with 968 cases and 336,191 controls, CD GWAS with 1,032 cases and 336,127 controls, and UC GWAS with 2,439 cases and 460,494 controls. The TIM-3 dataset was used as the exposure (n = 31,684). Four MR methods, namely, inverse-variance weighting (IVW), MR-Egger regression, weighted median, and weighted mode, were used in this study. Comprehensive sensitivity analyses were conducted to estimate the robustness of identified associations and the potential impact of horizontal pleiotropy.

Results: Our studies show that TIM-3 is significantly associated with CD using the IVW method (OR = 1.001, 95% CI = 1.0002-1.0018, P-value = 0.011). We also found that TIM-3 may be a protective factor for AU although these results lacked significance (OR = 0.889, 95% CI = 0.631-1.252, P-value = 0.5). No association was observed between the genetic predisposition to particular TIM-3 and susceptibility to AS or UC in this study. No potential heterogeneities or directional pleiotropies were observed in our analyses.

Conclusion: According to our study, a small correlation was observed between TIM-3 expression and CD susceptibility. Additional studies in different ethnic backgrounds will be necessary to further explore the potential roles and mechanisms of TIM-3 in CD.

Keywords: Crohn's disease; Mendelian randomization; TIM-3; anterior uveitis; causal inference.

Grants and funding

This study was supported by the Wenzhou Science and Technology Bureau (Y20190625) and the Zhejiang Province Natural Science Foundation of China (LQ21H180011).