Longitudinal Assessment of LDL Immune Complexes and Type 1 Diabetes Complications

描述(由申请人提供)：本申请响应PAR-09-247：正在进行的主要临床研究的辅助研究，以促进NIDDK任务中的科学兴趣领域(R01)。此外，这项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)研究的既定基础设施，而且建立在之前得到NIH资助的题为“糖尿病血管疾病的标记物和机制”的项目赠款(P01 HL55782)的基础上，该项目于2008年终止。简而言之，我们建议完成二次数据分析，以研究520名DCCT/EDIC参与者中与微血管和大血管并发症相关的低密度脂蛋白免疫复合体(IC)测量的流行病学，这些生物标志物在跨越22年的四个时间点进行测量。初步数据表明，与已确定的危险因素包括低密度脂蛋白水平、血红蛋白A1c和白蛋白排泄率相比，ox低密度脂蛋白-IC和年龄-低密度脂蛋白-IC是1型糖尿病动脉粥样硬化的更强的预测因子。然而，对纵向数据进行适当的分析是至关重要的。拟议的纵向研究将使我们能够确定哪些低密度脂蛋白-IC修饰在预测糖尿病并发症的发生方面最重要，并可能使我们揭示预防并发症发生的可能机制。这项拟议研究的目的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)治疗是否会导致低密度脂蛋白-IC水平下降。这项拟议研究的目的2是测试氧化低密度脂蛋白、年龄低密度脂蛋白和丙二醛低密度脂蛋白免疫复合体预测1型糖尿病患者微血管和大血管疾病结果的假设；确定这些新的风险因素相对于已有的风险因素的区别力；确定能够预测感兴趣的结果的生物标志物；以及确定严格的血糖控制、降脂治疗或ACE抑制剂或ARB治疗是否改变了基线低密度脂蛋白-IC水平和疾病结果之间的关系。1型糖尿病是一种慢性衰弱疾病，最终会导致并发症，导致严重的发病率和死亡率。如果特定的低密度脂蛋白-IC在1型糖尿病并发症的发展中起关键作用，那么特定的低密度脂蛋白-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可能提供一种机制，为治疗开发提供靶向。 公共卫生相关性：低密度脂蛋白免疫复合体(IC)是一种新的生物标志物，可预测1型糖尿病患者的并发症。因此，利用之前在对1型糖尿病患者进行的大型研究中收集的关于这些生物标记物的数据，我们建议确定特定的低密度脂蛋白免疫复合体是否与1型糖尿病患者的常见并发症有关，包括心脏病、外周血管疾病、肾脏疾病和眼病。如果低密度脂蛋白-IC在1型糖尿病并发症的发展中起关键作用，那么特异性的低密度脂蛋白-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可能提供一种机制，为治疗开发提供靶向。

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.