Mediation Effect of Neutrophil Lymphocyte Ratio on Cardiometabolic Risk Factors and Cardiovascular Events

Neutrophil to lymphocyte ratio (NLR), an inflammatory biomarker, is associated with cardiovascular events (CVEs), but its causal pathway is unknown. We aimed to explore the extent to which NLR is directly associated with CVEs or mediated through diabetes mellitus (DM), hypertension (HT) and creatinine (Cr). The study used data on 2,501 subjects from the Electricity Generating Authority of Thailand cohort 2002-2012. Two causal pathways A: NLR→(DM→Cr→HT)→CVEs and B: NLR→(DM → HT→Cr)→CVEs were constructed. A generalized structural equation model and 1,000-replication bootstrapping were applied. The incidence rate of CVE was 8.8/1000/year. Prevalence rates of HT, DM, and chronic kidney disease were 45.1%, 23.6%, and 16.5%, respectively. The total effect of NLR on CVEs was explained partly (44%) by a direct effect and partly (56%) by an indirect effect through DM, HT and Cr. For pathway A, the direct OR of NLR on CVE was 1.25 (95% CI: 1.13, 1.39); the ORs for the indirect effects of NLR on CVEs mediated through DM, Cr, and poor-controlled HT were 1.06 (95% CI: 1.01, 1.11), 1.01 (95% CI: 1.00, 1.02), and 1.07 (95% CI: 1.01, 1.14) respectively. Results were similar for pathway B. Our findings demonstrate that roughly half of the relationship between NLR and CVEs may be mediated through DM, HT and Cr.