The causal relationship in hypertensive encephalopathy: mechanistic analysis of five specific circulating cytokines.

OBJECTIVES

To investigate the causal relationship between genetically predicted levels of five circulating cytokines - CXCL11, IL-2, IL-4, leukemia inhibitory factor (LIF), and neurotrophin-3 (NT-3) - and the risk of hypertensive encephalopathy using a two-sample Mendelian randomization (MR) approach.

METHODS

Single nucleotide polymorphisms (SNPs) strongly associated with each cytokine (p<5 × 10-8) were selected from publicly available GWAS data. Summary statistics for HE were obtained from the FinnGen biobank (endpoint: I9_HYPERTENC). MR analyses were conducted using inverse-variance weighted (IVW), MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses included heterogeneity testing, MR-Egger intercept assessment, and leave-one-out analysis.

RESULTS

Genetically higher levels of IL-2 (OR=0.35, 95 % CI: 0.13-0.99, p=0.043), IL-4 (OR=0.50, 95 % CI: 0.30-0.85, p=0.010), and NT-3 (OR=0.46, 95 % CI: 0.28-0.75, p=0.0038) were significantly associated with lower risk of HE. CXCL11 showed a significant positive association with HE risk (OR=2.79, 95 % CI: 1.26-6.20, p=0.028). LIF displayed a non-significant trend toward protection (OR=0.43, p=0.060). Results were consistent across sensitivity analyses with no evidence of pleiotropy or heterogeneity.

CONCLUSIONS

This Mendelian randomization study provides evidence that genetically determined levels of IL-2, IL-4, and NT-3 are protective against hypertensive encephalopathy, while CXCL11 is a risk factor. These cytokines may serve as potential biomarkers or therapeutic targets for HE.