The CTLA-4 rs231775 GG genotype is associated with favorable 90-day survival in Caucasian patients with sepsis

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.

CTLA-4 Genetic Variants Predict Survival in Patients with Sepsis

“…The present study included 644 prospectively enrolled adult Caucasian patients with sepsis. Patients were recruited from three surgical intensive care units (ICUs) through the GENOSEP database of the Department of Anesthesiology at the University Medical Center Goettingen [20]. Enrolled patients were identified by daily screening of the three ICUs according to the actual sepsis definitions and guidelines [1,30].…”

“…Enrolled patients were identified by daily screening of the three ICUs according to the actual sepsis definitions and guidelines [1,30]. The exclusion criteria were defined in previous studies [20,31] and were an age below 18 years, pregnancy, therapy with immunosuppressive drugs or chemotherapy, myocardial infarction within six weeks before enrollment, human immunodeficiency virus (HIV) infection, chronic heart failure classified as New York Heart Association (NYHA) stage IV, end-stage incurable disease, a persistent vegetative state (apallic syndrome), and a “Do Not Treat” (DNT) or “Do Not Resuscitate” (DNR) order. Upon enrollment, blood was drawn within 72 h, and the patients were followed up for 90 days unless previously dismissed or deceased.…”

“…Coinhibitory immune checkpoint proteins, such as PD-1 and CTLA-4, have been reported to play key roles in the course of sepsis [13,17,18,19], and our working group has revealed genetic associations of their genes with the survival of septic patients [9,20]. Our recent study revealed that the CTLA-4 rs231775 GG genotype, which was reported to have an attenuated inhibitory effect on T cell reactions [21] and was associated with greater T cell activation and proliferation and autoimmune diseases [22], was also associated with favorable 90- and 28-day survival in septic patients compared to the survival rates of A allele carriers at this position [20].…”

Favorable 90-Day Mortality in Obese Caucasian Patients with Septic Shock According to the Sepsis-3 Definition

“…All patient data were recorded using clinical report forms (CRFs) and organized in the GENOSEP database, a database that was previously described and primarily used for genetic association studies with the clinical phenotype of sepsis [12]. Collected data included patient baseline characteristics such as gender, age in years, baseline Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE II) score as well as additional variables including relevant parameters for organ-specific SOFA subscores and the following comorbidities: arterial hypertension, chronic obstructive pulmonary disease (COPD), renal dysfunction, insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), and history of cancer.…”

“…Exogenous factors such as diagnostic procedures or antibiotic treatment strategies are still up for discussion and are often inconsistent [8,9]. Likewise, endogenous patient factors, such as the individual immune status, host genetic factors, microbiological findings and existing comorbidities, have gained attention in recent years [10][11][12][13][14][15]. In particular, the effect of obesity, one of the most common comorbidities in critically ill patients, on sepsis and septic shock has been examined in various studies [16,17].…”