title: Evaluation of Circulating Markers of Neutrophil Extracellular Trap (NET) Formation as Risk Factors for Diabetic Retinopathy in a Case-Control Association Study.
abstract: Background:Inflammatory stimuli can induce neutrophils to release nuclear DNA combined with histones into the extracellular space, forming neutrophil extracellular traps. Because inflammation contributes to diabetic retinopathy, it is plausible that neutrophil extracellular trap formation actively occurs in diabetic retinopathy. This case-control study investigated the clinical relevance of circulating levels of neutrophil extracellular trap components as risk factors of diabetic retinopathy, and further evaluated whether glucose induced neutrophil extracellular trap formation in vitro using whole blood from healthy volunteers.Methods:Circulating levels of DNA-histone complexes, cell free double-stranded DNA, and polymorphonuclear neutrophil elastase, considered to be markers of neutrophil extracellular trap formation, were measured in patients with diabetic retinopathy (n=28) and without (n=62) and in 28 healthy controls.Results:Circulating DNA-histone complex and polymorphonuclear neutrophil elastase levels were significantly increased in patients with diabetic retinopathy compared with those without retinopathy. Multivariable logistic regression analysis, adjusted for glycated hemoglobin levels and fasting blood glucose, revealed that DNA-histone complex and polymorphonuclear neutrophil elastase levels were significant independent risk factors of retinopathy. In vitro experiments also showed that glucose significantly increased markers of neutrophil extracellular trap formation in a dose-dependent manner.Conclusions:Markers of neutrophil extracellular trap formation were independent risk factors of diabetic retinopathy. This finding provides a new insight into the potential therapeutic and preventive approaches to dampen neutrophil extracellular trap formation.
authors.affiliation: Department of Laboratory Medicine and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Laboratory Medicine and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: J-E
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Gu
authors.affiliation: Department of Laboratory Medicine and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Yoo
authors.affiliation: Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
authors.forename: Y I
authors.initials: YI
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
authors.forename: I S
authors.initials: IS
authors.lastname: Nam-Goong
authors.affiliation: Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
authors.forename: E S
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: H K
authors.initials: HK
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003930:Diabetic Retinopathy / Q000097:blood*; D065206:Extracellular Traps / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000378:metabolism*; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D010196:Pancreatic Elastase