CCR1 as a potential regulator of neutrophil-mediated pathogenesis in post-acute ischemic stroke: a multi-omics Mendelian randomization

BACKGROUND: The genetic and immunological mechanisms underlying post-acute ischemic stroke (IS) remain incompletely understood, particularly those involving neutrophil-mediated inflammation. This study aimed to identify genes associated with IS using a multi-omics Mendelian randomization framework. METHODS: Summary-data-based Mendelian Randomization (SMR) was used to identify upstream genetic regulators of neutrophil-driven pathogenesis. We systematically screened 949 neutrophil-related genes using SMR analyses across multi-omics quantitative trait loci (QTL) datasets (methylation, expression, and protein). We then validated temporal expression patterns in independent IS cohorts and constructed a diagnostic nomogram to assess clinical discrimination. RESULTS: Multi-omics SMR analysis identified CCR1, DEFA4, SH2B3 and CDKN1A as potential genes associated with IS risk. In independent clinical validation cohorts, CCR1 and DEFA4 were consistently upregulated in the peripheral blood of IS patients. Notably, CCR1 emerged as a central hub gene; its expression exhibited a potential association with neutrophil abundance (R = 0.31) and functional hyperactivation pathways, including chemotaxis and cytotoxicity. Furthermore, a diagnostic nomogram integrating CCR1 and DEFA4 demonstrated high discriminatory power (AUC = 0.875), underscoring their potential as precision biomarkers. CONCLUSIONS: Identified as a potential neutrophil-related genetic factor, CCR1 is associated with ischemic injury and may contribute to neutrophil chemotaxis and functional hyperactivation. Consequently, targeting CCR1 offers a precision therapeutic strategy to attenuate neuroinflammation.