Increased Neutrophil to Lymphocyte Ratio Exacerbates Metabolic Syndrome via Alanine Aminotransferase: Evidence from NHANES and Mendelian Randomization

Inhalt:
Neutrophil-to-lymphocyte ratio (NLR) is a diagnostic and prognostic marker in various diseases, but its link to metabolic syndrome (Mets) remains unclear. Analyzing 32,922 participants (2005-2018) in the National Health and Nutrition Examination Survey (NHANES) database, we categorized log-transformed NLR into quartiles based on the median and interquartile range. The LogNLR associations with Mets and components were analyzed using Kaplan-Meier, logistic regression, and restricted cubic splines (RCS) curves. Alanine aminotransferase (ALT) was selected as a mediator from 80 metabolic enzymes. Causal links between NLR, ALT, and Mets were assessed via mediation and multivariable Mendelian randomization (MR). The results showed that high NLR levels were associated with increased all-cause, diabetes, and cardiovascular mortality in Mets patients (all P<0.001). Elevated NLR increased the risk of Mets by 19.4% (OR_Q4:Q1 = 1.194, 95% CI: 1.070, 1.321, P = 0.001), though no significant in younger individuals (P = 0.095). MR analysis found no direct causal effect of NLR on Mets (IVW, P=0.638) nor reverse causal relationship (IVW, P = 0.7). Instead, the impact of NLR on Mets appeared predominantly mediated through elevated ALT levels (β=0.012, SE=0.004, P = 0.006). Thus, elevated NLR may contribute to Mets development potentially mediated by ALT. Findings require cautious interpretation due to MR heterogeneity; further mechanistic studies are needed.