Mediators of the Association Between Stroke and Blood Cells: A Two‐Step Multivariable Mendelian Randomization Study

Abstract

ABSTRACT Background and Purpose Stroke remains one of the leading causes of death and disability worldwide, posing a serious global health burden. Identifying reliable and easily accessible biomarkers for stroke risk is therefore of great clinical importance. The complete blood count (CBC) is a routine and widely available hematological test that provides key information about blood cell components, including red blood cells, white blood cells, and platelets. These parameters collectively reflect systemic conditions such as inflammation, infection, and coagulation, which are known to play critical roles in stroke pathogenesis. Recent evidence suggests that certain CBC parameters may be associated with an increased risk of stroke; however, the nature and direction of these associations remain unclear. This study aims to comprehensively evaluate the relationship and potential causal links between individual CBC parameters and the risk of stroke. Methods Our analysis encompassed 6736 participants from the NHANES dataset (2011–2016). We utilized a suite of statistical techniques: multivariable logistic regression, Weighted Quantile Sum (WQS) regression, restricted cubic spline analysis, and Mendelian randomization. These methods were applied to assess the link between blood cell metrics (CBC) and stroke, considering a broad spectrum of covariates such as age, race, socioeconomic status, BMI, lifestyle factors (smoking, alcohol consumption, physical activity), serum calcium levels, hypertension, and diabetes. Stroke cases were ascertained using a dedicated questionnaire, and an extensive array of CBC parameters was examined. This study aims to systematically assess the association between CBC parameters and stroke risk, and explore their potential causal relationship using multivariate statistical analysis and genetic epidemiological methods. Results Initial analysis revealed significant disparities in age, education, income, hypertension, and diabetes between the stroke and nonstroke cohorts. CBC, notably LBXRDW, LBXHCT, LBXHGB, and LBXMCHSI, emerged as independent predictors of stroke. WQS regression underscored a positive association between these indices and stroke risk, which was attenuated after adjusting for confounders. Restricted cubic spline analysis uncovered significant nonlinear correlations for LBXRDW and LBXMCHSI with stroke events. Mendelian randomization further suggested potential causal links between specific CBC (e.g., mean erythrocyte hemoglobin concentration, red blood cell distribution width) and stroke, albeit with variable correlation directions. Sensitivity analyses, including heterogeneity inspection and pleiotropy testing, reinforced the robustness of these findings. Conclusions This study reveals the multi‐layered and complex associations between CBC parameters and stroke risk, emphasizing the need to comprehensively consider hematological characteristics and various confounding factors in stroke‐related research. These findings contribute to a deeper understanding of the mechanisms underlying stroke onset and provide a theoretical basis and new insights for future early screening and personalized interventions for stroke risk.