The Role of TLR4 Gene Polymorphisms in the Development of Severe Sepsis in Oncohematological Patients with Acquired Immunological Disorders

Background and AimsSepsis is a common complication in patients with hematological malignancies that occurs during chemotherapy treatment, which in turn leads to acquired immunodeficiency. In recent years, increasing attention has been paid to the role of genetic predisposition in the development of sepsis and its outcomes. Toll-like receptor 4 (TLR4), which plays a key role in the recognition of lipopolysaccharide, a component of the cell wall of gram-negative bacteria, is one of the most studied candidate genes for sepsis susceptibility. Genetic alterations in the TLR4 gene can influence the expression and functional activity of the receptor, modulate the intensity of the inflammatory response, and, consequently, determine the severity of the infection.MethodsThe study group consisted of oncohematological patient samples (n = 148) with severe sepsis in the Department of Anesthesiology and Intensive Care at the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology. DNA samples isolated from peripheral blood and buccal epithelium, which were subjected to Sanger sequencing, were used as material for the study.ResultsThe rs11536889 polymorphism in the noncoding region of the TLR4 gene was studied in 148 patients with sepsis, of whom 73 (49.4%) had sepsis and 75 (50.6%) had septic shock. The rs11536889 polymorphism of the TLR 4 gene was associated with the development of septic shock (χ2 = 4.9; p = 0.027; odds ratio [OR] = 2.4 [1.1–5.3]; OR = 1.49 [1.1–2.1]).Since this allelic variant is located in the noncoding region of the TLR4 gene, it should not directly alter protein conformation. However, polymorphisms in introns and/or UTRs (untranslated regions) may influence transcription and translation. This polymorphism may regulate TLR4 expression and influence the response to bacterial cell wall lipopolysaccharide, likely through binding to microRNA. Consequently, the rs11536889 genetic variation may influence the development of systemic inflammation.ConclusionsIdentification of the rs11536889 polymorphism in the TLR4 gene in patients with hematological malignancies scheduled for high-dose chemotherapy and/or prior to hematopoietic stem cell transplantation due to a high risk of developing acquired immune deficiency. This will allow for the identification of high-risk groups and patient stratification for more aggressive and personalized therapy.