Assoziation des regulierenden Polymorphismus rs11536889 im TLR4-Gen mit Organ-spezifischer Morbidität und Mortalität bei Patienten mit Sepsis

The regulatory toll-like receptor 4 genetic polymorphism rs11536889 is associated with renal, coagulation and hepatic organ failure in sepsis patients

by Luisa von Gruben
Doctoral thesis
Date of Examination:2020-09-29
Date of issue:2020-09-08
Advisor:Prof. Dr. Ashham Mansur
Referee:Prof. Dr. Ralf Dressel
Referee:Prof. Dr. Martin Oppermann
Persistent Address: http://dx.doi.org/10.53846/goediss-8178

 

 

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Abstract

English

Abstract Background Toll-like receptor 4 (TLR4), a lipopolysaccharide (LPS) receptor complex signal-transducing molecule, plays a crucial role in sensing LPS from gram-negative bacteria. TLR4 signaling pathway activation by LPS plays a major role in sepsis pathogenesis. A single nucleotide polymorphism, rs11536889, in the 3’-untranslated region of the TLR4 gene is thought to affect TLR4 translation. This study aimed to investigate whether organ failure in sepsis patients is related to the TLR4 rs11536889 genotype. Methods Adult Caucasian patients with sepsis from the intensive care unit of a university medical center were followed up for 90 days, and organ failure was recorded as the primary outcome variable. Blood samples were collected at enrollment for TLR4 rs11536889 genotyping. Sepsis-related organ failure assessment (SOFA) scores were quantified at sepsis onset and throughout the observational period to monitor organ failure. Results A total of 210 critically ill patients with sepsis were enrolled into this study. Wild-type GG was compared to GC/CC. During their stay in the intensive care unit, GG patients presented significantly higher SOFA scores than did C allele carriers (7.9 ± 4.5 and 6.8 ± 4.2, respectively; p = 0.0005). Analysis of organ-specific SOFA sub-scores revealed significant differences in three organ systems: renal, coagulation and hepatic (p = 0.0005, p = 0.0245 and p < 0.0001, respectively). Additionally, the rs11536889 polymorphism was associated with a higher incidence of gram-negative infections. Conclusions These results offer the first evidence that TLR4 rs11536889 is a useful marker of organ failure in patients with sepsis.
Keywords: Sepsis; TLR4
 
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