A Functional Polymorphism-Mediated Disruption of EGR1/ADAM10 Pathway Confers the Risk of Sepsis Progression

Abstract

Increasing evidence has indicated that single nucleotide polymorphisms (SNPs) are related to the susceptibility of sepsis and might provide potential evidence for the mechanisms of sepsis. Our recent preliminary study showed that the ADAM10 genetic polymorphism was clinically associated with the development of sepsis, and little is known about the underlying mechanism. The aim of this study was to confirm the association between the ADAM10 promoter rs653765 G→A polymorphism and the progression of sepsis and to discover the underlying mechanism. Clinical data showed that the rs653765 G→A polymorphism was positively correlated with the development of sepsis, as evidenced by a multiple-center case-control association study with a large sample size, and showed that EGR1 and ADAM10 levels were associated well with the different subtypes of sepsis patients. In vitro results demonstrated that the rs653765 G→A variants could functionally modulate ADAM10 promoter activity by altering the binding of the EGR1 transcription factor (TF) to the ADAM10 promoter, affecting the transcription and translation of the ADAM10 gene. Electrophoretic mobility shift assay (EMSA) followed by chromatin immunoprecipitation (ChIP) assay indicated the direct interaction. Functional studies further identified that the EGR1/ADAM10 pathway is important for the inflammatory response. EGR1 intervention in vivo decreased host proinflammatory cytokine secretion and rescued the survival and tissue injury of the mouse endotoxemia model. IMPORTANCE Sepsis is characterized as life-threatening organ dysfunction, with unacceptably high mortality. Evidence has indicated that functional SNPs within inflammatory genes are associated with susceptibility, progression, and prognosis of sepsis. These mechanisms on which these susceptible sites depended often suggest the key pathogenesis and potential targets in sepsis. In the present study, we confirmed that a functional variant acts as an important genetic factor that confers the progression of sepsis in a large sample size and in multiple centers and revealed that the variants modulate the EGR1/ADAM10 pathway and influence the severity of sepsis. We believe that we provide an important insight into this new pathway involving the regulation of inflammatory process of sepsis based on the clinical genetic evidence, which will enhance the understanding of nosogenesis of sepsis and provide the potential target for inflammation-related diseases.

The -172A>G polymorphism in ADAM17 promoter region enhances its binding to EGR1 and confers susceptibility to sepsis progression

“…Additionally, we found that the inhibition of EGR1 can reduce the in ammatory response and improve the survival of LPS-induced endotoxemia mice, which was consistent with our previous study [48]. However, another study reported that Egr-1 de ciency via gene knock-out did not positively affect survival and plasma levels of TNF in endotoxemic mice [49].…”

Association of ADAM10 gene variants with sporadic Parkinson's disease in Chinese Han population

“…26 The ADAM10 rs514049-rs653765 CA promoter haplotype could functionally modulate ADAM10 promoter activity by altering the binding of the EGR1 (early growth response protein 1) transcription factor to the ADAM10 promoter, affecting the transcription of ADAM10. 26,37 One study containing 10 people with mild cognitive impairments (MCIs), 25 AD patients, and 10 healthy controls (HCs) in a Brazilian population, found that plasma ADAM10 levels were significantly higher in AD patients than in HCs, while the concentration of plasma ADAM10 in PD patients remains unknown. 38 variants have also been observed in AD, 8,15,26,38 However, the role of ADAM10 in the occurrence and development of PD is unclear.…”

The -172A>G Polymorphism in ADAM17 Promoter Region Enhances Its Binding to EGR1 and Confers Susceptibility to Sepsis Progression

“…Province. The patients were enrolled in the study if they met the following inclusion criteria: 1) the patients were older than 18 years of age and belonged to the Chinese Han population; 2) the diagnosis of sepsis, severe sepsis, or septic shock was established according to the International Sepsis De nitions Conference [30]; and 3) the patients had a probability of survival greater than 24 hours. Patients were excluded from this study if they had diabetes, malignant tumors, human immunode ciency virus, or autoimmune diseases or were pregnant, readmitted to a hospital or receiving immunosuppressive therapy, corticosteroid therapy or chemoradiotherapy.…”

“…EGR1 antisense oligonucleotide (As-ODN) (5'-TACCGTCGCCGGTTC-3') was constructed to inhibit EGR1 by targeting the corresponding DNA sequence. The EGR1 sense ODN (S-ODN) (5'-TCGTGCCGCTGCCAT-3') was used as a negative control [30,31]. All ODNs were synthesized by Takara Biomedical Technology Co., Ltd.…”