Elevated IL-36γ levels and `IL36G` gene variants linked to increased essential hypertension risk

Essential hypertension (EH) remains a leading cause of cardiovascular morbidity and mortality, yet its precise etiology is complex and not fully understood. Current treatments often manage symptoms but don't always address underlying inflammatory drivers. Cytokines are increasingly recognized for their crucial role in regulating blood pressure and vascular inflammation. IL-36γ, a pro-inflammatory cytokine from the IL-1 superfamily, has been implicated in various cardiovascular conditions, but its specific involvement in essential hypertension has remained unclear, representing a critical knowledge gap this study aimed to address.

Researchers conducted a case-control study involving 264 patients diagnosed with essential hypertension and 264 age- and sex-matched normotensive controls. Serum IL-36γ levels were quantified using enzyme-linked immunosorbent assay (ELISA). IL36G gene polymorphisms (rs11690399 and rs11683399) were assessed using the PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) method. Mendelian randomization was employed to investigate a potential causal relationship between elevated IL-36γ and hypertension risk, and ROC (Receiver Operating Characteristic) analysis evaluated IL-36γ's diagnostic performance as a biomarker.

Patients with essential hypertension exhibited significantly elevated serum IL-36γ levels compared to normotensive controls (p < 0.0001). Genotyping analysis revealed a significant association between IL36G rs11690399 and rs11683399 polymorphisms and susceptibility to essential hypertension. Specifically, combination genotypes (GT + TT) for rs11690399 and (TG + GG) for rs11683399 conferred an elevated disease risk. The T allele of rs11690399 was associated with a 2.6-fold increased risk, and the G allele of rs11683399 with a 1.9-fold increased risk of essential hypertension.

Significantly higher levels of IL-36γ were observed in individuals with these variant genotypes, indicating a strong genotype-phenotype correlation. Haplotype analysis identified T-T and T-G as risk haplotypes for essential hypertension. Mendelian randomization further supported a causal relationship between increased IL-36γ and hypertension risk (OR = 1.0066; 95% CI: 1.0028-1.0104, p < 0.0001). Furthermore, IL-36γ demonstrated strong diagnostic performance for essential hypertension with an AUC of 0.862 in ROC analysis, suggesting its potential as a clinical biomarker.