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

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

Lulu Sun #  1 , Daoxia Guo #  1   2 , Yiming Jia  1 , Mengyao Shi  1 , Pinni Yang  1 , Yu Wang  1 , Fanghua Liu  1 , Zhengbao Zhu  3 , Jin Zheng  4
Affiliations

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

Lulu Sun et al. Thromb J. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
An overview of the present mendelian randomization study design. The assumption is that (1) instrumental variables are associated with intercellular adhesion molecule 4 levels, (2) instrumental variables are not associated with confounders, (3) and instrumental variables affect ischemic stroke or its subtypes only through the effects on intercellular adhesion molecule 4 levels Abbreviations: SNP, single-nucleotide polymorphism; IVW, inverse-variance weighted; MR-RAPS, mendelian randomization robust adjusted profile score
Fig. 2
Fig. 2
Main analysis for associations of genetically determined ICAM-4 levels with ischemic stroke and its subtypes Abbreviations: ICAM-4, intercellular adhesion molecule 4; IVW, inverse-variance weighted; SNP, single-nucleotide polymorphism; SE: standard error; OR, odds ratio; 95% CI, 95% confidence interval
Fig. 3
Fig. 3
Associations between genetic instruments of ICAM-4 and the risks of ischemic stroke and cardioembolic stroke. The line indicates the estimate for the associations of intercellular adhesion molecule 4 (ICAM-4) levels with ischemic stroke and cardioembolic stroke using inverse-variance weighted method. Circles indicate associations of each genetic variant related to ICAM-4 levels with the risks of ischemic stroke and cardioembolic stroke. Genetic error bars indicate 95% confidence intervals A, ischemic stroke; B, cardioembolic stroke
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