Intercellular adhesion molecule 4 and ischemic stroke: a two-sample Mendelian randomization study

Lulu Sun; Daoxia Guo; Yiming Jia; Mengyao Shi; Pinni Yang; Yu Wang; Fanghua Liu; Zhengbao Zhu; Jin Zheng

doi:10.1186/s12959-023-00485-4

Intercellular adhesion molecule 4 and ischemic stroke: a two-sample Mendelian randomization study

Thromb J. 2023 Apr 11;21(1):40. doi: 10.1186/s12959-023-00485-4.

Authors

Lulu Sun^#¹, Daoxia Guo^#^{1

2}, Yiming Jia¹, Mengyao Shi¹, Pinni Yang¹, Yu Wang¹, Fanghua Liu¹, Zhengbao Zhu³, Jin Zheng⁴

Affiliations

¹ Department of Epidemiology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, 199 Renai Road, Industrial Park District, 215123, Suzhou, Jiangsu Province, China.
² School of Nursing, Medical College of Soochow University, Suzhou, China.
³ Department of Epidemiology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, 199 Renai Road, Industrial Park District, 215123, Suzhou, Jiangsu Province, China. zbzhu@suda.edu.cn.
⁴ Department of Neurology, Minhang Hospital, Fudan University, Shanghai, China. Zhengjin22163@fudan.edu.cn.

^# Contributed equally.

Abstract

Background: Experimental studies suggested that intercellular adhesion molecule 4 (ICAM-4) might be implicated in ischemic stroke, but the population-based evidence on the relationship between ICAM-4 and ischemic stroke were limited. Herein, we performed a two-sample Mendelian randomization (MR) analysis to investigate the associations of genetically determined plasma ICAM-4 with the risks of ischemic stroke and its subtypes.

Methods: A total of 11 single-nucleotide polymorphisms associated with ICAM-4 were selected as instrumental variables based on the genome-wide association studies (GWAS) with 3,301 European individuals. Summary-level data about ischemic stroke and its subtypes were obtained from the Multi-ancestry GWAS launched by the International Stroke Genetics Consortium. We used the inverse-variance weighted method followed by a series of sensitivity analyses to evaluate the associations of genetically determined ICAM-4 with the risks of ischemic stroke and its subtypes.

Results: Genetically determined higher ICAM-4 levels were significantly associated with increased risks of ischemic stroke (in the IVW method fitted to multiplicative random effects model: odds ratio [OR] per standard deviation [SD] increase, 1.04; 95% confidence interval [CI], 1.01-1.07; P = 0.006; in the IVW analysis with fixed effects model: OR per SD increase, 1.04; 95% CI, 1.01-1.07; P = 0.003) and cardioembolic stroke (in multiplicative random effects model: OR per SD increase, 1.08; 95% CI, 1.02-1.14; P = 0.004; in fixed effects model: OR per SD increase, 1.08; 95% CI, 1.03-1.13; P = 0.003). There was no association of ICAM-4 with the risks of large artery stroke and small vessel stroke. MR-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses with different MR methods further confirmed these findings.

Conclusions: We found positive associations of genetically determined plasma ICAM-4 with the risks of ischemic stroke and cardioembolic stroke. Future studies are needed to explore the detailed mechanism and investigate the targeting effect of ICAM-4 on ischemic stroke.

Keywords: Intercellular adhesion molecule 4; Ischemic stroke; Mendelian randomization; Risk.

Abstract

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