title: High concentrations of AGE-LDL and oxidized LDL in circulating immune complexes are associated with progression of retinopathy in type 1 diabetes.
abstract: OBJECTIVE
  To determine whether immunocomplexes (ICs) containing advanced glycation end product (AGE)-LDL (AGE-LDL) and oxidized LDL (oxLDL) contribute to the development of retinopathy over a 16-year period in subjects with type 1 diabetes.
  
  
  METHODS
  Levels of AGE-LDL and oxLDL in ICs were measured in 517 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Retinopathy was assessed by stereoscopic fundus photography. Cox proportional hazards models were used to assess the effect of AGE-LDL-ICs and oxLDL-ICs on retinopathy progression.
  
  
  RESULTS
  In unadjusted models, higher baseline levels of AGE-LDL-ICs and oxLDL-ICs significantly predicted progression of diabetic retinopathy outcomes. After adjustment by study-design variables (treatment group, retinopathy cohort, duration of type 1 diabetes, and baseline albumin excretion rate [AER], hemoglobin A(1c) (HbA(1c)), and Early Treatment Diabetic Retinopathy Study [ETDRS] score), one SD increase in IC levels was associated with 47% (hazard ratio [HR] 1.47 [95% CI 1.19-1.81]; AGE-LDL-IC) and 45% (1.45 [1.17-1.80]; oxLDL-IC) increased risk of developing proliferative diabetic retinopathy (PDR) and 37% (1.37 [1.12-1.66]; to both ICs) increased risk of progressing to severe nonproliferative retinopathy. Analyses were stratified by retinopathy cohort because results differed between primary and secondary cohorts. For AGE-LDL-ICs, HR for progression to PDR was 2.38 (95% CI 1.30-4.34) in the primary cohort and attenuated in the secondary cohort (1.29 [1.03-1.62]). Similar results were observed for oxLDL-ICs.
  
  
  CONCLUSIONS
  Increased levels of AGE-LDL and oxLDL in ICs are associated with increased risk for progression to advanced retinopathy in patients with type 1 diabetes, indicating that the antibody response to modified LDL plays a significant role in retinopathy progression.
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA. virellam@musc.edu
authors.forename: Maria F
authors.initials: MF
authors.lastname: Lopes-Virella
authors.forename: Nathaniel L
authors.initials: NL
authors.lastname: Baker
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Hunt
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Lyons
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Jenkins
authors.forename: Gabriel
authors.initials: G
authors.lastname: Virella
mesh_terms: D000328:Adult; D000419:Albuminuria / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D016016:Proportional Hazards Models; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D008078:Cholesterol, LDL; D006442:Glycated Hemoglobin; D017127:Glycation End Products, Advanced; D008077:Lipoproteins, LDL; C517652:hemoglobin A1c protein, human; C099252:oxidized low density lipoprotein