Abstract
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a surface protein on T cells, that has an inhibitory effect on the host immune reaction and prevents overreaction of the immune system. Because the functional single-nucleotide polymorphism (SNP) rs231775 of the CTLA-4 gene is associated with autoimmune diseases and because of the critical role of the immune reaction in sepsis, we intended to examine the effect of this polymorphism on survival in patients with sepsis. 644 septic adult Caucasian patients were prospectively enrolled in this study. Patients were followed up for 90 days. Mortality risk within this period was defined as primary outcome parameter. Kaplan-Meier survival analysis revealed a significantly lower 90-day mortality risk among GG homozygous patients (n = 101) than among A allele carriers (n = 543; 22% and 32%, respectively; p = 0.03565). Furthermore, the CTLA-4 rs231775 GG genotype remained a significant covariate for 90-day mortality risk after controlling for confounders in the multivariate Cox regression analysis (hazard ratio: 0.624; 95% CI: 0.399–0.975; p = 0.03858). In conclusion, our study provides the first evidence for CTLA-4 rs231775 as a prognostic variable for the survival of patients with sepsis and emphasizes the need for further research to reveal potential functional associations between CTLA-4 and the immune pathophysiology of sepsis.
Highlights
Sepsis is defined as a “life-threatening organ dysfunction caused by a dysregulated host response to infection[1]
The genotype distribution is consistent with Hardy-Weinberg equilibrium (p = 0.2156), and the observed minor allele frequency (MAF) almost equals the expected HapMap CEPH (CEU) MAF of 0.3931
Considering the complexity of the immune response in sepsis, it is important to examine factors involved in the activation and upregulation of the immune system, such as the coinhibitory checkpoint protein Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
Summary
Sepsis is defined as a “life-threatening organ dysfunction caused by a dysregulated host response to infection[1]. It is a significant public health care issue[2] and still a leading cause of death and critical illness in intensive care units (ICUs) worldwide[3]. PD-1 and CTLA-4 are suggested to play a key role in the host response over the course of sepsis[16,17]; these proteins function as concomitant inhibitory receptors within the process of T cell activation and proliferation[18]. Studies have reported that the rs231775 GG genotype is associated with higher T cell activation and proliferation and is, as previously stated, more frequent in Caucasian patients with the autoimmune diseases rheumatoid arthritis and Hashimoto thyroiditis[29]
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