Abstract
Hypertension, a common chronic disease worldwide, has an unclear causal relationship and association pattern with red cell distribution width (RDW), a prognostic marker for cardiovascular events. Traditional observational studies have struggled to clarify this relationship due to confounding factors and reverse causality. A mixed study design integrating observational and genetic evidence was adopted: observational analysis: based on data from National Health And Nutrition Examination Survey 2021 to 2023 (n = 5768), complex sampling-weighted multivariable logistic regression and restricted cubic splines were used to analyze the RDW-hypertension association, with subgroup interaction tests; causal inference: MR-PRESSO-adjusted Mendelian randomization (MR) analysis (hypertension GWAS: ukb-b-12493; RDW GWAS: ebi-a-GCST006804) was performed, using 56 strong instrumental variables (F > 10) to verify the causal direction, supplemented by sensitivity analyses including inverse-variance weighting (IVW) and MR-Egger. Each 1-unit increase in RDW was associated with a 13% increased risk of hypertension (OR = 1.13, 95% CI = 1.05-1.21) after adjustment for 12 covariates in the full model, with a nonlinear threshold effect (P for nonlinearity = .028): the association was stronger when RDW < 13.8% (OR = 1.29, P < .001). After MR-PRESSO adjustment, the IVW method confirmed that hypertension caused an increase in RDW (OR = 1.36, 95% CI = 1.03-1.79, P = .03), with no horizontal pleiotropy (Egger intercept = 0.973). Subgroup analysis showed that the RDW-hypertension association was significant in populations without a history of stroke (OR = 1.14) or coronary heart disease (OR = 1.14) but disappeared in patients with these conditions (interaction P < .05). This study is the first to explore the association between hypertension and RDW via MR-PRESSO-adjusted MR, providing evidence of a potential causal link where hypertension may contribute to increased RDW, and identifies a RDW threshold of 13.8%. RDW can serve as a prognostic marker for cardiovascular events and may be a reference indicator for monitoring the risk of hypertension in populations without cardiovascular complications, pending further validation of its role in the pathological mechanism of hypertension.