Bidirectional Mendelian randomization of leukocyte counts, renal function, and Lipocalin-2 Levels: disentangling the genetic links, causal pathways and cardiovascular outcomes.

Lipocalin-2 (LCN2) level, leukocyte count (LC), and renal function are key biomarkers linked to inflammation and metabolism. We aimed to explore the genetic determinants, causal associations, and long-term outcome effects of LCN2 levels. Phenotypic associations, genome-wide association studies (GWASs), linkage disequilibrium score regression (LDSC), and Mendelian randomization (MR) analyses for genetic correlation and causal associations between LCN2, LC, and estimated glomerular filtration rate (eGFR) were performed in 8208, 117,666, and 117,666 Taiwan Biobank participants, respectively. Long-term outcome analyses were performed for LCN2 in 481 patients with coronary artery disease (CAD). Elevated LCN2 levels were associated with older age, male sex, and altered metabolic parameters. GWAS of LCN2 levels identified genome-wide significant loci on LCN2, GSDMA, and MYB. LDSC revealed a limited number of shared loci between LCN2 level, LC and eGFR rather than broad polygenic overlap. MR analyses showed weighted genetic risk scores for LC and eGFR were significantly associated with LCN2 levels, which remain significant even at multivariate analysis (p = 0.0123 and p = 0.0010, respectively). Sensitivity analyses confirmed the robustness of causal estimates. Kaplan-Meier survival and Cox regression analyses further indicated that elevated LCN2 level, especially when combined with C-reactive protein levels, is an independent predictor of all-cause mortality and combined cerebral and cardiovascular event rates in CAD patients. Taken together, these results indicate that circulating LCN2 is largely a downstream marker of immune activation and impaired renal function. Elevated LCN2 levels independently predict poor long-term outcomes of CAD.