Longitudinal Assessment of LDL Immune Complexes and Type 1 Diabetes Complications

LDL 免疫复合物和 1 型糖尿病并发症的纵向评估

• 批准号: 8092481
• 负责人: KELLY J HUNT
• 金额: $ 15.15万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8092481
• 关键词: Age; Albumins; Ancillary Study; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Antigen-Antibody Complex; Antihypertensive Agents; Area; Atherosclerosis; Biological Markers; Blood Vessels; Carotid Arteries; Cholesterol; Chronic; Clinical Research; Complications of Diabetes Mellitus; Data; Data Analyses; Data Set; Development; Diabetes Mellitus; Disease; Disease Outcome; Disease Pathway; Dyslipidemias; Enrollment; Epidemiology; Excretory function; Eye diseases; Funding; Funding Mechanisms; Future; Glycosylated hemoglobin A; Guidelines; Heart Diseases; Human; Hypertension; Immune; Individual; Inflammatory; Insulin-Dependent Diabetes Mellitus; Intervention; Kidney Diseases; Knowledge; LDL Cholesterol Lipoproteins; Lipids; Lipoproteins; Longitudinal Studies; Low-Density Lipoproteins; Measurement; Measures; Medial; Mission; Modification; Morbidity - disease rate; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Outcome; Oxidative Stress; Participant; Patients; Peripheral Vascular Diseases; Play; Population; Population Study; Predictive Value; Program Research Project Grants; Randomized; Relative (related person); Research; Research Infrastructure; Research Personnel; Resources; Retinal Diseases; Risk Factors; Role; Sampling; Serum; Surrogate Markers; Testing; Thick; Time; United States National Institutes of Health; Vascular Diseases; base; blood glucose regulation; cohort; coronary artery calcification; diabetes control; disorder risk; epidemiology study; interest; longitudinal analysis; low density lipoprotein inhibitor; meetings; mortality; novel; oxidized low density lipoprotein; prevent; public health relevance; research study; therapy development

DESCRIPTION (provided by applicant): This application is responsive to PAR-09-247: Ancillary Studies to Major Ongoing Clinical Research Studies to Advance Areas of Scientific Interest within the Mission of the NIDDK (R01). Moreover, the proposed study not only capitalizes on the established infrastructure of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, but builds of off a previously supported NIH funded Program Project Grant (P01 HL55782) entitled "Markers and Mechanisms of Vascular Disease in Diabetes" that terminated in 2008. In brief, we propose to complete secondary data analysis to study the epidemiology of LDL immune complex (IC) measurements in relation to micro- and macro-vascular complications in 520 DCCT/EDIC participants with these biomarkers measured at four time points spanning 22 years. Preliminary data suggest that oxLDL-IC and AGE-LDL-IC are stronger predictors of atherosclerosis in type 1 diabetes than established risk factors including LDL cholesterol levels, hemoglobin A1c and albumin excretion rate. However, proper analysis of the longitudinal data is essential. The longitudinal studies proposed will allow us to determine which LDL-IC modifications are the most important in predicting development of complications in diabetes and may allow us to uncover possible mechanisms through which the development of complications could be prevented. Aim 1 of the proposed study is to determine whether glucose control, lipid lowering therapy or treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), which are known to decrease lipids and/or oxidative stress, leads to a decrease in LDL-IC levels. Aim 2 of the proposed study is to test the hypothesis that ox-LDL, AGE-LDL and MDA-LDL immune complexes predict micro- and macro-vascular disease outcomes in individuals with type 1 diabetes; to determine the discriminatory power of these novel risk factors relative to established risk factors; to identify biomarker panels able to predict outcomes of interest; and to determine whether tight glucose control, lipid lowering therapy or treatment with ACE inhibitors or ARBs modifies the relationship between baseline LDL-IC levels and disease outcomes. Type 1 diabetes is a chronic debilitating disease which ultimately results in complications which cause major morbidity and mortality. If specific LDL-IC are playing a critical role in the development of type 1 diabetes complications, not only could specific LDL-IC serve as biomarkers of future disease risk, but knowledge of their role on the disease pathway may provide a mechanism to target for therapy development. PUBLIC HEALTH RELEVANCE: LDL immune complexes (IC) are new biomarkers which may predict complications in patients with type 1 diabetes. Therefore, using data on these biomarkers previously collected as part of a large ongoing study on individuals with type 1 diabetes we propose to determine whether specific LDL immune complexes are associated with common complications in individuals with type 1 diabetes including heart disease, peripheral vascular disease, renal disease and eye disease. If LDL-IC are playing a critical role in the development of type 1 diabetes complications, not only could specific LDL-IC serve as biomarkers of future disease risk, but knowledge of their role on the disease pathway may provide a mechanism to target for therapy development.

描述（由申请人提供）：本申请响应 PAR-09-247：主要正在进行的临床研究的辅助研究，以推进 NIDDK (R01) 使命内的科学兴趣领域。此外，拟议的研究不仅利用了糖尿病控制和并发症试验/糖尿病干预和并发症流行病学 (DCCT/EDIC) 研究的现有基础设施，而且建立在先前支持的 NIH 资助的计划项目拨款 (P01 HL55782) 的基础上，题为“糖尿病血管疾病的标记和机制”，该拨款于 2008 年终止。简而言之，我们 提议完成二次数据分析，以研究与 520 名 DCCT/EDIC 参与者的微血管和大血管并发症相关的 LDL 免疫复合物 (IC) 测量的流行病学，这些生物标志物在 22 年的四个时间点测量。初步数据表明，oxLDL-IC 和 AGE-LDL-IC 比 LDL 胆固醇水平、血红蛋白 A1c 和白蛋白排泄率等既定危险因素更能预测 1 型糖尿病动脉粥样硬化。然而，对纵向数据的正确分析至关重要。所提出的纵向研究将使我们能够确定哪些 LDL-IC 修饰对于预测糖尿病并发症的发展最为重要，并可能使我们能够揭示预防并发症发展的可能机制。拟议研究的目标 1 是确定血糖控制、降脂治疗或血管紧张素转换酶 (ACE) 抑制剂或血管紧张素受体阻滞剂 (ARB) 治疗（已知可降低血脂和/或氧化应激）是否会导致 LDL-IC 水平降低。拟议研究的目标 2 是检验以下假设：ox-LDL、AGE-LDL 和 MDA-LDL 免疫复合物可预测 1 型糖尿病患者的微血管和大血管疾病结果；确定这些新风险因素相对于既定风险因素的歧视力；识别能够预测感兴趣结果的生物标志物组；并确定严格的血糖控制、降脂治疗或 ACE 抑制剂或 ARB 治疗是否会改变基线 LDL-IC 水平与疾病结果之间的关系。 1 型糖尿病是一种慢性衰弱性疾病，最终会导致并发症，导致严重的发病率和死亡率。如果特定的 LDL-IC 在 1 型糖尿病并发症的发展中发挥着关键作用，那么特定的 LDL-IC 不仅可以作为未来疾病风险的生物标志物，而且了解它们在疾病途径中的作用也可以为治疗开发的目标提供机制。 公共卫生相关性：LDL 免疫复合物 (IC) 是新的生物标志物，可预测 1 型糖尿病患者的并发症。因此，利用之前收集的这些生物标志物的数据，作为对 1 型糖尿病患者进行的大型研究的一部分，我们建议确定特定的 LDL 免疫复合物是否与 1 型糖尿病患者的常见并发症有关，包括心脏病、周围血管疾病、肾脏疾病和眼部疾病。如果 LDL-IC 在 1 型糖尿病并发症的发展中发挥着关键作用，那么特定的 LDL-IC 不仅可以作为未来疾病风险的生物标志物，而且了解它们在疾病途径中的作用也可以为治疗开发的目标提供机制。