Genetic insights into the relationship between immune cell characteristics and ischemic stroke: A bidirectional Mendelian randomization study

Abstract

Background and purposeIschemic stroke, a major contributor to global disability and mortality, is underpinned by intricate pathophysiological mechanisms, notably neuroinflammation and immune cell dynamics. Prior research has identified a nuanced and often paradoxical link between immune cell phenotypes and ischemic stroke susceptibility. The aim of this study was to elucidate the potential causal links between the median fluorescence intensity (MFI) and morphological parameters (MP) of 731 immune cell types and ischemic stroke risk.MethodsBy analyzing extensive genetic datasets, we conducted comprehensive Mendelian randomization (MR) analyses to discern the genetic correlations between diverse immune cell attributes (MFI and MP) and ischemic stroke risk.ResultsOur study identified key immune cell signatures linked to ischemic stroke risk. Both B cells and T cells, among other immune cell types, have a bidirectional influence on stroke risk. Notably, the regulatory T‐cell phenotype demonstrates significant neuroprotective properties, with all odds ratio (OR) values and confidence intervals (CIs) being less than 1. Furthermore, CD39 phenotype immune cells, particularly CD39+ CD8+ T cells (inverse variance weighting [IVW] OR 0.92, 95% CI 0.87–0.97; p = 0.002) and CD39+ activated CD4 regulatory T cells (IVW OR 0.93, 95% CI 0.90–0.97; p < 0.001), show notable neuroprotection against ischemic stroke.ConclusionThis investigation provides new genetic insights into the interplay between various immune cells and ischemic stroke, underscoring the complex role of immune processes in stroke pathogenesis. These findings lay a foundation for future research, which may confirm and expand upon these links, potentially leading to innovative immune‐targeted therapies for stroke prevention and management.

Causality of genetically proxied immunophenotypes on cardiovascular diseases: a Mendelian randomization study

“…These findings suggest that CD39 plays an important role not only in inhibiting thrombosis, but also in reducing neuroinflammation. A recent study has found that CD39 emerges as a key immunomodulatory component for neuroprotection in ischemic stroke on CD39+ activated CD4 Treg cells ( 47 ). Similar to our results, an elevated proportion of CD39+ resting T cells, signifying a reduced proportion of activated CD39+ T cells, exerts an adverse influence on stroke.…”

Causal relationships between immune cell phenotypes and lung adenocarcinoma: A bidirectional two‐sample Mendelian randomization study

“… 27 , 28 Linkage disequilibrium (LD) among SNPs was calculated based on the European 1000 Genome Reference panel. 29 To reduce the impact of LD and select independent SNPs, the clumping process (a threshold of LD r 2 < 0.001 within 10 000 kb distance) was conducted using PLINK software (version 1.90). 28 Weak IVs with an F‐statistic of <10 were excluded from further analysis.…”

“…However, due to the exploratory nature of the study and our rigorous screening of IVs, adjusted significance levels were not considered the primary criteria for determining causal relationships, as in other similar MR studies. 29 , 34 …”

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

“…Following an ischemic event, there is a notable accumulation of B cells in the affected area, where they actively engage in the immune response ( 10 , 11 ). A previous Mendelian randomization (MR) study revealed that distinct B-cell subtypes exhibit differential impacts on IS, and this study posits that specific B-cell phenotypes, such as CD24+ B-cell phenotypes, potentially confer neuroprotection, in contrast to IgD+CD24-B cells, which may predispose individuals to a heightened risk of IS ( 12 ). Although this investigation offers preliminary insights, the intricate interplay and roles of IgD and CD24 phenotypes within the context of IS have yet to be comprehensively delineated, underscoring the critical necessity for this research.…”