IL-10 diplotype and septic shock: Genotype-Phenotype associations with hemodynamic dysfunction and IL-10 expression

Early identification of patients with sepsis who are at increased risk of developing septic shock remains a major clinical challenge. Although genetic variation within the IL-10 locus has been associated with immune regulation, the relationship between the rs1518111-rs1554286 haplotype architecture, inflammatory phenotype, and hemodynamic status has not been fully characterized. This study investigated whether IL-10 haplotypes are associated with progression to septic shock and their relationship with blood pressure and systemic and urinary IL-10 concentrations.

In this prospective observational study, 492 adult patients with sepsis admitted to the intensive care unit were enrolled according to the Sepsis-3 criteria. Genotyping of IL-10 rs1518111 and rs1554286 was performed using TaqMan allelic discrimination assays. Linkage disequilibrium, haplotypes, and diplotypes were reconstructed using Haploview and PHASE software. Serum and urinary IL-10 concentrations were quantified by enzyme-linked immunosorbent assay. Associations between genetic variants, clinical phenotypes, and septic shock were evaluated using multivariable logistic regression adjusted for age, sex, admission white blood cell count, and Sequential Organ Failure Assessment score. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis.

The two loci demonstrated strong linkage disequilibrium (D' = 1.00, r ² = 0.903). Compared with the reference heterozygous diplotype (C-G/T-A), the homozygous variant diplotype (T-A/T-A) was independently associated with septic shock (adjusted OR, 6.30; 95% CI, 3.68-10.78; P < 0.001), whereas the homozygous wild-type diplotype (C-G/C-G) was associated with lower odds (adjusted OR, 0.28; 95% CI, 0.14-0.61; P < 0.001). Variant homozygotes exhibited higher serum and urinary IL-10 concentrations and lower blood pressure than wild-type carriers. Serum IL-10 yielded an AUC of 0.851, while a combined clinical-genetic model achieved an AUC of 0.889 (95% CI, 0.820-0.958).

Variation within the IL-10 rs1518111-rs1554286 Diplotype block was associated with susceptibility to septic shock, higher IL-10 concentrations, and lower arterial blood pressure in patients with sepsis. Integration of IL-10 diplotype information with routinely available clinical and laboratory variables modestly improved discrimination for septic shock. These findings support further evaluation of IL-10 genetic variation as a complementary biomarker for risk stratification in larger, multicenter cohorts.