GPR174 was associated with the immune response and sepsis susceptibility in Chinese Han population / 中华急诊医学杂志

ABSTRACT

Objective:Dysregulated host immune responses contribute to the pathogenesis of sepsis. G protein-coupled receptor 174 (GPR174) was found to be involved in the immune responses and associated with the susceptibility to autoimmune diseases. This study aimed to investigate the association of GPR174 variants with sepsis susceptibility and the contribution of GPR174 in sepsis development.Methods:From May 2005 to December 2017, a total of 575 sepsis patients and 579 non-septic controls admitted to our Emergency ICU were enrolled in this case-control study. The non-synonymous SNP rs3827440 in GPR174 was genotyped using TaqMan Real-time PCR assays on ABI7900 platform. Then the correlation between rs3827440 and serum levels of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) were investigated in septic patients. Gpr174-deficient mice were generated and subjected to cecal ligation and puncture (CLP). The concentrations of inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA).Results:Rs3827440 TT/T genotype in GPR174 was positively associated with sepsis risk after logistic regression analysis adjusted for sex [odds ratio ( OR) = 1.68, 95% confidence interval ( CI) 1.19-2.20, P = 0.0004]. IL-6 and TNF-α serum levels in female TT and male T allele carriers of septic patients were significantly higher than those in female CC and male C allele carriers ( P < 0.05). Preclinical validation of Gpr174 gene was performed in Gpr174 knockout (KO) mice using CLP models. Gpr174 KO mice had higher survival rate. Moreover, Gpr174 KO mice had significantly decreased serum concentrations of IL-1β, IL-6 and TNF-α compared with WT mice, while the levels of IL-10 was increased ( P < 0.01). Conclusions:GPR174 as a novel sepsis susceptibility gene in Chinese Han population is involved in the development and physiopathology of sepsis.