Association between genetic polymorphisms in the autophagy-related 5 gene promoter and the risk of sepsis

Yiming Shao,Yujie Cai,Jianghao Zhao,Junbing He,Hui Mai,Zihan Yin,Qinghui Liao,Feng Chen,Lili Cui,Yanfang He,Wenying Zhang,Shoubao Tao,Yao Lin,Yuhua Chen

doi:10.1038/s41598-017-09978-5

Yiming Shao, Yujie Cai + Show 12 more

Open Access

https://doi.org/10.1038/s41598-017-09978-5

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Abstract

Previous studies demonstrated significant roles of autophagy in the pathogenesis of sepsis, but few studies focused on the effect of autophagy-related SNPs on sepsis susceptibility. In this present study, five polymorphisms of ATG5/ATG16L1 were investigated for the possible risk on sepsis in a Chinese Han population. Our results showed that ATG5 expression levels decreased with the severity of sepsis, and rs506027 T > C and rs510432 G > A were associated with sepsis progression and mortality. Moreover, the rs506027 TT and rs510432 GG carriers also exhibited increased expression levels of ATG5. Functional assays showed that ATG5 knockdown elevated the secretion of pro-inflammatory cytokines in THP-1 cells, and the extracted mononuclear cell of the risk C-A carriers exhibited decreased ATG5 expression levels, leading to enhanced releases of TNF-α and IL-1β under LPS stimulation in vitro. Furthermore, ATG5 T-G haplotype mutation showed higher promoter activities compared to C-A haplotype mutation, suggesting the effect of these SNPs on ATG5 gene transcription. Taken together, these results above indicated that these two ATG5 promoter polymorphisms may be functional and clinically significant for sepsis progression, underscoring its potentially therapeutic implications for sepsis and other inflammatory diseases.

Highlights

Previous studies demonstrated significant roles of autophagy in the pathogenesis of sepsis, but few studies focused on the effect of autophagy-related SNPs on sepsis susceptibility
It have been demonstrated that macrophages deficient in the autophagy proteins autophagy-related 5 (ATG5) and autophagy-related 16-like 1 (ATG16L1) showed markedly higher production of pro-inflammatory cytokines after lipopolysaccharide stimulation[21, 22], and defects in these autophagy-related proteins was correlated with an increased septic response and lethality in murine modes of sepsis induced by cecal ligation puncture[23,24,25]
These lines of evidence demonstrate that ATG5 and ATG16L1, which have been implicated in autophagy initiation and regulation, play a significant role in the pathogenic mechanism underlying the development of sepsis

Summary

Introduction

Previous studies demonstrated significant roles of autophagy in the pathogenesis of sepsis, but few studies focused on the effect of autophagy-related SNPs on sepsis susceptibility. It have been demonstrated that macrophages deficient in the autophagy proteins ATG5 and ATG16L1 showed markedly higher production of pro-inflammatory cytokines after lipopolysaccharide stimulation[21, 22], and defects in these autophagy-related proteins was correlated with an increased septic response and lethality in murine modes of sepsis induced by cecal ligation puncture[23,24,25]. These lines of evidence demonstrate that ATG5 and ATG16L1, which have been implicated in autophagy initiation and regulation, play a significant role in the pathogenic mechanism underlying the development of sepsis. Functional assays of these genetic polymorphisms were explored in vitro to evaluate the possible associations between these polymorphisms and sepsis

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