Abstract
Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is a coinhibitory checkpoint protein expressed on the surface of T cells. A recent study by our working group revealed that the rs231775 single nucleotide polymorphism (SNP) in the CTLA-4 gene was associated with the survival of patients with sepsis and served as an independent prognostic variable. To further investigate the impact of CTLA-4 genetic variants on sepsis survival, we examined the effect of two functional SNPs, CTLA-4 rs733618 and CTLA-4 rs3087243, and inferred haplotypes, on the survival of 644 prospectively enrolled septic patients. Kaplan–Meier survival analysis revealed significantly lower 90-day mortality for rs3087243 G allele carriers (n = 502) than for AA-homozygous (n = 142) patients (27.3% vs. 40.8%, p = 0.0024). Likewise, lower 90-day mortality was observed for TAA haplotype-negative patients (n = 197; compound rs733618 T/rs231775 A/rs3087243 A) than for patients carrying the TAA haplotype (n = 447; 24.4% vs. 32.9%, p = 0.0265). Carrying the rs3087243 G allele hazard ratio (HR): 0.667; 95% confidence interval (CI): 0.489–0.909; p = 0.0103) or not carrying the TAA haplotype (HR: 0.685; 95% CI: 0.491–0.956; p = 0.0262) remained significant covariates for 90-day survival in the multivariate Cox regression analysis and thus served as independent prognostic variables. In conclusion, our findings underscore the significance of CTLA-4 genetic variants as predictors of survival of patients with sepsis.
Highlights
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [1] and remains a leading cause of death and critical illness worldwide [2]
This study aimed to investigate the impact of these two functional single nucleotide polymorphisms (SNPs) and inferred haplotypes compound of rs733618, rs231775, and rs3087243 on the 90-day mortality of septic patients in order to further reveal the role of CTLA-4 genetic variants in sepsis
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, and a “Do Not Treat” (DNT) or “Do Not Resuscitate”
Summary
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [1] and remains a leading cause of death and critical illness worldwide [2]. The multifaceted pathophysiology of sepsis and sepsis-related organ dysfunction is highly diverse and has been intensively investigated in the recent past [5]. Host genetic characteristics, such as gene variants encoding innate immune effectors or inflammatory mediators, seem to contribute considerably to the disease course and sepsis outcome [6,7,8,9]. The genetic component of host susceptibility to sepsis is clearly polygenetic [10], and identification of responsible variants will help elucidate the pathophysiology and biology of the disease. Identifying sepsis-associated genetic variants and evaluating their impacts on gene expression, protein function and host physiology will potentially reveal future targets for sepsis treatment [11]
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