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<b>Background</b>: Previous studies have reported the fundamental role of immunoregulatory proteins in the clinical phenotype and outcome of sepsis. This study investigated two functional single nucleotide polymorphisms (SNPs) of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), which has a negative stimulatory function in the T cell immune response. <b>Methods</b>: Patients with sepsis (<i>n</i> = 712) were prospectively enrolled from three intensive care units (ICUs) at the University Medical Center Goettingen since 2012. All patients were genotyped for the TIM-3 SNPs rs1036199 and rs10515746. The primary outcome was 28-day mortality. Disease severity and microbiological findings were secondary endpoints. <b>Results</b>: Kaplan–Meier survival analysis demonstrated a significantly lower 28-day mortality for TIM-3 rs1036199 AA homozygous patients compared to C-allele carriers (18% vs. 27%, <i>p</i> = 0.0099) and TIM-3 rs10515746 CC homozygous patients compared to A-allele carriers (18% vs. 26%, <i>p</i> = 0.0202). The TIM-3 rs1036199 AA genotype and rs10515746 CC genotype remained significant predictors for 28-day mortality in the multivariate Cox regression analysis after adjustment for relevant confounders (adjusted hazard ratios: 0.67 and 0.70). Additionally, patients carrying the rs1036199 AA genotype presented more Gram-positive and <i>Staphylococcus epidermidis</i> infections, and rs10515746 CC homozygotes presented more <i>Staphylococcus epidermidis</i> infections. <b>Conclusion</b>: The studied TIM-3 genetic variants are associated with altered 28-day mortality and susceptibility to Gram-positive infections in sepsis.