The CD14 rs2569190 TT Genotype Is Associated with an Improved 30-Day Survival in Patients with Sepsis: A Prospective Observational Cohort Study

Abstract

According to previous investigations, CD14 is suggested to play a pivotal role in initiating and perpetuating the pro-inflammatory response during sepsis. A functional polymorphism within the CD14 gene, rs2569190, has been shown to impact the pro-inflammatory response upon stimulation with lipopolysaccharide, a central mediator of inflammation in sepsis. In this study, we hypothesized that the strong pro-inflammatory response induced by the TT genotype of CD14 rs2569190 may have a beneficial effect on survival (30-day) in patients with sepsis. A total of 417 adult patients with sepsis (and of western European descent) were enrolled into this observational study. Blood samples were collected for rs2569190 genotyping. Patients were followed over the course of their stay in the ICU, and the 30-day mortality risk was recorded as the primary outcome parameter. Sepsis-related organ failure assessment (SOFA) scores were quantified at sepsis onset and throughout the observational period to monitor organ failure as a secondary variable. Moreover, organ support-free days were evaluated as a secondary outcome parameter. TT-homozygous patients were compared to C-allele carriers. Kaplan-Meier survival analysis revealed a higher 30-day mortality risk among C-allele carriers compared with T homozygotes (p = 0.0261). To exclude the effect of potential confounders (age, gender, BMI and type of infection) and covariates that varied at baseline with a p-value < 0.2 (e.g., comorbidities), we performed multivariate Cox regression analysis to examine the survival time. The CD14 rs2569190 C allele remained a significant covariate for the 30-day mortality risk in the multivariate analysis (hazard ratio, 2.11; 95% CI, 1.08-4.12; p = 0.0282). The 30-day mortality rate among C allele carriers was 23%, whereas the T homozygotes had a mortality rate of 13%. Additionally, an analysis of organ-specific SOFA scores revealed a significantly higher SOFA-Central nervous system score among patients carrying the C allele compared with T-homozygous patients (1.9±1.1 and 1.6±1.0, respectively; p = 0.0311). In conclusion, CD14 rs2569190 may act as a prognostic variable for the short-term outcome (30-day survival) in patients with sepsis.

Association of CD14 -159 Gene Polymorphism with Characteristics and Outcome of Diffuse Large B-cell Lymphomas

“…Despite frequent findings of poor outcome in patients with CD14 -159 TT genotype, Mansur and coworkers reported improved survival in those patients. 26 Similarly, superior survival in critically ill patients after burn injury was noticed in CD14 -159 TT carriers. 27 In summary, our study indicates the association of CD14 -159 T allele and the presence of extranodal DLBCL and elevated CRP at diagnosis, both previously established as unfavorable clinical parameters.…”

Sepsis Diagnostics in the Era of “Omics” Technologies

“…Similarly pro-and anti-inflammatory cytokines like the interleukin-1 (IL-1) gene family, interleukin-6 (IL-6) and interleukin-10 (IL-10) are associated with different outcomes of septic patients (Fang et al, 1999). Genomic variants of candidate genes involved in pathogen recognition and signal transduction of inflammatory pathways like CD14, Toll-like receptors (TLRs), lipopolysaccharide binding protein (LBP), interleukin-1 receptor-associated kinase (IRAK 4), IRAK 1 may also contribute to the incidence, severity and mortality of infectious complications in the critically ill (Hubacek et al, 2001;Feterowski et al, 2003;Medvedev et al, 2003;Sutherland et al, 2005;Arcaroli et al, 2006;Khor et al, 2007;Chien et al, 2008;Mansur et al, 2015). In addition, it has been recognized that protein cascades involved in the pathophysiology of sepsis, such as the coagulation cascade, represent strong genomic candidate markers for association studies (Hermans et al, 1999).…”

The role of genetics and antibodies in sepsis

“…A meta-analysis of 17 studies has shown that carriers of C alleles are exposed to 1.72 odds ratio for septic shock (P=0.03) but this association existed mainly for Asian populations and not for European populations (22). In a recent study of 417 adult patients of western European descent, 30-day survival was 77% among patients with the CT or TT genotype and 87% among patients with the TT genotype (P=0.0261) (23).…”