The Association between the rs3747406 Polymorphism in the Glucocorticoid-Induced Leucine Zipper Gene and Sepsis Survivals Depends on the SOFA Score

Abstract

The variability in mortality in sepsis could be a consequence of genetic variability. The glucocorticoid system and the intermediate TSC22D3 gene product-glucocorticoid-induced leucine zipper-are clinically relevant in sepsis, which is why this study aimed to clarify whether TSC22D3 gene polymorphisms contribute to the variance in sepsis mortality. Blood samples for DNA extraction were obtained from 455 patients with a sepsis diagnosis according to the Sepsis-III criteria and from 73 control subjects. A SNP TaqMan assay was used to detect single-nucleotide polymorphisms (SNPs) in the TSC22D3 gene. Statistical and graphical analyses were performed using the SPSS Statistics and GraphPad Prism software. C-allele carriers of rs3747406 have a 2.07-fold higher mortality rate when the sequential organ failure assessment (SOFA) score is higher than eight. In a multivariate COX regression model, the SNP rs3747406 with a SOFA score ≥ 8 was found to be an independent risk factor for 30-day survival in sepsis. The HR was calculated to be 2.12, with a p-value of 0.011. The wild-type allele was present in four out of six SNPs in our cohort. The promoter of TSC22D3 was found to be highly conserved. However, we discovered that the C-allele of rs3747406 poses a risk for sepsis mortality for SOFA Scores higher than 6.

Keywords: GILZ; glucocorticoid-induced leucine zipper; hydrocortisone; personalized medicine; rs3747406; sepsis; single-nucleotide polymorphism.

Figure 1

(a–c): The 30-day survival rate in sepsis using the Kaplan–Meier analysis. (a). The survival curve of the T-allele carriers (blue) and C-allele carriers (red) for the single nucleotide polymorphism (SNP) rs3747406 (HR = 1.36; p = 0.215). (b): Septic patients with a sequential organ failure assessment (SOFA) score ≥ 6 and T-allele (blue), and septic patients with a SOFA score ≥ 6 and C-allele (red) for the SNP rs3747406 (HR = 1.90; p = 0.017). (c): Septic patients with a SOFA score ≥ 8 and T-allele (blue), and septic patients with a SOFA score ≥ 8 and C-allele (red) for the SNP rs3747406 (HR = 2.027; p = 0.011).

Figure 2

Quantitative glucocorticoid-induced leucine zip (GILZ) mRNA expression in all rs3747406 SNP genotypes on day 1 and day 8 of sepsis diagnosis. The quantitative gene expression was normalized to the housekeeping gene ß-actin, computed using the 2^−∆CT method. TT day 1 to day 8 n = 87; ** p = 0.0059; TC/CC day 1 to day 8 n = 13, ** p = 0.0093.