Longitudinal Association Between Endothelial Dysfunction, Inf lammation, and Clotting Biomarkers With Subclinical Atherosclerosis in Type 1 Diabetes: An Evaluation of the DCCT/EDIC Cohort DOI: 10.2337/dc14-2877 OBJECTIVE There is considerable interest in identifying biomarkers that predict high risk for the development of macrovascular complications in patients with diabetes. Therefore, the longitudinal association between subclinical atherosclerosis as measured by internal carotid artery intima-medial thickness (IMT) and acute- phase reactants, cytokines/adipokines, thrombosis, and adhesion molecules was examined. RESEARCH DESIGN AND METHODS Biomarkers were measured at four time points over 20 years in 886 DCCT/EDIC participants with type 1 diabetes. Four composite scores were created by com- bining Z scores generated from within the dataset of individual biomarkers: acute- phase reactants (fibrinogen, C-reactive protein), thrombosis (fibrinogen, active and total plasminogen activator inhibitor [PAI]-1), cytokines/adipokines (tumor necrosis factor receptor-1 and -2, active and total PAI-I, IL-6), and endothelial dysfunction (soluble intracellular adhesion molecule-1, soluble vascular cell ad- hesion molecule-1, and soluble E-selectin). Internal carotid IMT was measured at EDIC years 1, 6, and 12, with elevated IMT defined at each time point as being in the upper quintile of its distribution. RESULTS Logistic regression models indicate that while individual biomarkers were not predictive of or associated with subclinical atherosclerosis, composite scores of acute-phase reactants (odds ratio [OR] 2.78 [95% CI 1.42–5.42]), thrombolytic factors (OR 2.83 [95% CI 1.45–5.52]), and cytokine/adipokines (OR 2.83 [95% CI 1.48–5.41]) measured at our final time point EDIC years 8–11 were associated with higher levels of atherosclerosis at EDIC year 12, but findings were not consistent at early time points. The endothelial dysfunction score was not appreciably predic- tive of or associated with subclinical atherosclerosis at any of the time points measured. CONCLUSIONS The pathophysiologic relationship between higher biomarkers levels and progres- sion of subclinical atherosclerosis remains unclear. 1 Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 2 Ralph H. Johnson VA Medical Center, Charles- ton, SC 3 Biostatistics Center, The George Washington University, Washington DC 4 Department of Medicine and Laboratory Ser- vices, Medical University of South Carolina, Charleston, SC 5 Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC Corresponding author: Kelly J. Hunt, huntke@musc .edu. Received 3 December 2014 and accepted 15 March 2015. This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ suppl/doi:10.2337/dc14-2877/-/DC1. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. Kelly J. Hunt, 1,2 Nathaniel L. Baker, 1 Patricia A. Cleary, 3 Richard Klein, 3,2 Gabriel Virella, 5 Maria F. Lopes-Virella, 3,2 and the DCCT/EDIC Group of Investigators Diabetes Care 1 EPIDEMIOLOGY/HEALTH SERVICES RESEARCH Diabetes Care Publish Ahead of Print, published online April 7, 2015