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. 2024 May 28:15:1405108.
doi: 10.3389/fneur.2024.1405108. eCollection 2024.

Effects of immune cells on ischemic stroke and the mediating roles of metabolites

Haoxiang Hu  1 , Mi Zhou  1 , Yunhan Zhao  1 , Jiesheng Mao  1 , Xiaokai Yang  1
Affiliations

Effects of immune cells on ischemic stroke and the mediating roles of metabolites

Haoxiang Hu et al. Front Neurol. .

Abstract

Objective: Previous studies have not shown an association between IgD-CD24-B-cell absolute count (IgD-CD24-AC) and ischemic stroke (IS). Our study aimed to assess the causal effect of IgD-CD24-AC on IS and to explore the role of ascorbic acid 2-sulfate (AA2S) as a potential mediator.

Methods: Our study was based on the largest available genome-wide association study (GWAS). Inverse variance weighting (IVW), MR-Egger, weighted median (WMN), simple mode, and weighted mode methods were used to assess causal effects, with IVW as the primary outcome. Subsequently, we further performed a two-step MR analysis to evaluate whether AA2S mediated this causal effect. In addition, several sensitivity analyses were conducted to evaluate heterogeneity, including Cochran's Q test, the MR-Egger intercept test, the MR-PRESSO global test, and the leave-one-out analysis.

Results: Using the IVW approach, the risk ratio of IgD-CD24-AC to IS was estimated to be 1.216 (95% CI = 1.079-1.371, p = 0.001). This result was supported by the WMN method (OR = 1.204, 95% CI = 1.020-1.421, p = 0.028) and the MR-Egger method (OR = 1.177, 95% CI = 0.962-1.442, p = 0.133). We also observed the same trend with the simple model and weighted model. Furthermore, the proportion of genetically predicted IgD-CD24-AC mediated through AA2S levels was 3.73%.

Conclusion: Our study revealed a causal relationship between IgD-CD24-AC and IS, a small part of which was mediated by AA2S. These findings offer critical insights for developing immune-targeted therapies in the future and lay a strong foundation for advancements in precision medicine.

Keywords: AA2S; IgD-CD24-AC; Mendelian randomization; immunology; ischemic stroke; metabolite.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The flowchart of our MR analysis. IgD-CD24-AC, IgD-CD24-B-Cell absolute count, AA2S, Ascorbic Acid 2-Sulfate.
Figure 2
Figure 2
Graphs illustrate the associations examined in this study. (A) Total effect “beta. All” of IgD-CD24-AC with ischemic stroke. (B) Total effect de-composed as (i) mediated effect using a two-step approach “beta12” = beta1 × beta2 (where “beta1” is the total effect of IgD-CD24-AC on AA2S and “beta2” is the effect of AA2S on ischemic stroke effect) (ii) direct effect = “total effect” − “mediated effect” (beta. All-beta12). The mediated ratio is the indirect effect divided by the total effect. IgD-CD24-AC, IgD-CD24-B Cell absolute count, AA2S, Ascorbic Acid 2-Sulfate.
Figure 3
Figure 3
Scatter plot of genetic association between IgD-CD24-AC, AA2S, and IS. (A) Association of IgD-CD24-AC with IS; (B) Association of IgD-CD24-AC with AA2S; (C) Association of AA2S with IS. The slope and direction of the straight line represent the magnitude and direction of the causal relationship. IgD-CD24-AC, IgD-CD24-B Cell absolute count, AA2S, Ascorbic Acid 2-Sulfate.
Figure 4
Figure 4
Forest plot of genetic association between IgD-CD24-AC and IS.
Figure 5
Figure 5
Forest plot to visualize the causal effects of AA2S with IgD-CD24-AC and ischemic stroke. IgD-CD24-AC, IgD-CD24-B Cell absolute count, AA2S, Ascorbic Acid 2-Sulfate.
Figure 6
Figure 6
Schematic diagram of the AA2S mediation effect. IgD-CD24-AC, IgD-CD24-B Cell absolute count, AA2S, Ascorbic Acid 2-Sulfate.
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