Determining the Risk of Developing Severe Sepsis Using Genetic Profiling of Innate Immunity Genes

Background and AimsThe immune response to an infectious agent is regulated by a complex network of signaling pathways involving numerous genes encoding inflammatory mediators, proteins of the innate and adaptive immune systems, and cell surface receptors of the first line of immune defense (neutrophils, macrophages, dendritic cells, etc.) (e.g., Toll-like receptors [TLRs]). Polymorphisms in these genes can determine the genetic variability of the systemic immune response and, consequently, the variability of clinical manifestations and outcomes of sepsis.MethodsWe analyzed DNA samples (n = 154) of oncohematological patients of the anesthesiology and intensive care unit with severe sepsis. Polymorphisms of the TLR4: c.*1205G>A; TNF-α: −308G>A; HAVCR1: p.Leu179Pro; p.T207A; CD14: −159C>T; IL18: 137G>C; 607C>A; BCL2: −938 C>A was detected using capillary Sanger sequencing.ResultsThe studies revealed the following: Polymorphism of the TLR4 gene: *1205G>A (odds ratio [OR] = 0.43 (0.2–0.9) (χ2 = 5.7, p = 0.021)). HAVCR1:T207A (OR = 0.42 (0.2–0.86) (χ2 = 5,8, p = 0.008)) increases the likelihood of developing septic shock. Polymorphism of the TNF-α:-308G>A (OR = 2.8(1.07–7.18)(χ2 = 6.3,p = 0.012)); HAVCR1: T207A (OR = 0.28(0.1–0.8) (χ2 = 7.6,p = 0.006)); BCL2: −938 C>A (OR = 0.4(0.18–0.9)(χ2 = 5.0, p = 0.012)), the likelihood of developing sepsis-associated acute kidney injury with the need for renal replacement therapy increases. In the presence of polymorphisms IL18: −137G>C (OR = 2.8 (1.2–6.6) (χ2 = 5.5, p = 0.009)); IL18: - 607C>A (OR = 0.34 (0.13–0.86) (χ2 = 5.7, p = 0.006)), the probability of developing acute respiratory distress syndrome increases.The absence of CD14 polymorphism: −159C>T (OR = 0.35 (0.16–0.78) (χ2 = 6.9, p = 0.004)) is associated with an increased likelihood of a long (more than 14 days) stay in the intensive care unit and the development of a “chronic critical condition.” Polymorphisms in the HAVCR1 gene: L179P (OR = 4.8 (1.37–16.6) (χ2 = 7.1, p = 0.004)) are associated with the likelihood of developing an unfavorable outcome (28-day mortality) increases.ConclusionsBased on the obtained results, the detection of polymorphisms in immune response genes and cytokines demonstrates high statistical significance, which may facilitate the identification of patients at risk for severe sepsis. For this category of patients, earlier transfer to the intensive care unit (ICU) is recommended to ensure timely initiation of risk-adapted, specialized, and high-tech care.