Re-evaluating the role of HDL in coronary artery disease (RETRO HDL)

 描述(由申请人提供)：与普通人群相比，1型糖尿病(T1D)患者患冠状动脉疾病(CAD)的风险大大增加，尽管传统的血脂和其他心血管风险因素只有很小的差异。尽管高密度脂蛋白胆固醇(高密度脂蛋白胆固醇)水平在T1D患者中普遍升高，但仍可反向预测冠心病风险。令人惊讶的是，对我们的糖尿病并发症流行病学(EDC)研究的18年随访分析显示，在女性中，冠心病发病率增加，高密度脂蛋白胆固醇(&gt；80 mg/dl)高度升高，而在这些女性中，没有注意到超过50 mg/dL的渐进保护措施。在男性中，尽管只有两个人的高密度脂蛋白水平高于80 mg/dL，但最初的强烈反相关关系在整个高密度脂蛋白胆固醇水平范围内都是成立的。因此，我们假设，这些明显相互矛盾的发现在高密度脂蛋白-C存在的情况下风险增加，反映了T1D的高密度脂蛋白功能受损。事实上，关于高密度脂蛋白-C功能障碍的假说，就其最关键的活动--反向胆固醇运输而言，早就在T1D中提出，尽管它还没有使用目前可用的高密度脂蛋白功能的新测量方法进行正式测试。最近报道的结合珠蛋白(HP)2等位基因与糖尿病的CAD发病率之间的关联也被认为，至少部分与这些个体的高密度脂蛋白功能受损，即胆固醇反向运输受损有关。幽门螺杆菌是一种急性期血浆蛋白，其主要功能是结合游离血红蛋白，从而抑制血红素铁的释放，从而减轻血红蛋白引起的组织氧化损伤。在T1D中，我们发现HP2-2显著增加了冠心病的风险，并且随着HP2等位基因数目的增加，风险呈线性增加的趋势。此外，在我们的HAPE干预研究中，高密度脂蛋白介导的胆固醇外流随着HP2等位基因的数量线性减少，而维生素E改善了HP2-2携带者的外流。考虑到这些数据，我们的目标是使用新的复杂方法来确定：a)与非糖尿病对照组(总体和性别)相比，T1D患者的高密度脂蛋白功能(类固醇外流)是否受损；b)高密度脂蛋白功能预测T1D患者冠心病的能力；以及c)高密度脂蛋白功能在多大程度上解释已报道的T1D患者HP-CAD的相关性。因此，我们建议使用一种经过充分验证的方法来量化高密度脂蛋白与巨噬细胞的流出能力，并用最先进的高密度脂蛋白颗粒浓度/大小和高密度脂蛋白的蛋白质货物(提供关于高密度脂蛋白的抗炎和抗氧化特性的信息)来补充这些研究。蛋白质组学分析虽然在本质上更具探索性，但将提供关于高密度脂蛋白抗炎/抗氧化特性的数据，这将是非常有意义的，因为炎症/氧化应激在动脉粥样硬化的发展中发挥作用，而且幽门螺杆菌是一种具有抗氧化特性的急性期蛋白质。因此，通过这项研究，我们的目的是进一步了解影响高密度脂蛋白对T1D患者心脏保护作用的因素，并阐明性别差异以及与HP2等位基因相关的冠心病风险增加的机制。

 DESCRIPTION (provided by applicant): Individuals with type 1 diabetes (T1D) are at greatly increased risk of coronary artery disease (CAD) compared to the general population, despite only minor differences in traditional lipid and other cardiovascular risk factors. Although generally elevated in T1D patients, high density lipoprotein cholesterol (HDL-C) levels still inversely predict CAD risk. Surprisingly, analyses of the 18-year follow-up of our Epidemiology of Diabetes Complications (EDC) study showed an increased CAD incidence with highly elevated (>80 mg/dL) HDL-C in women, in whom no progressive protection above 50 mg/dL was noted. In men, the original strong inverse relationship held throughout the range of HDL-C levels, though only two had HDL-C above 80 mg/dL. We therefore hypothesize that these apparently contradictory findings of elevated risk in the presence of high HDL- C reflect impaired HDL functionality in T1D. Indeed, the hypothesis of dysfunctional HDL-C in terms of its most critical activity, reverse cholesterol transport, has long been proposed in T1D, although it has not been formally tested using currently available novel measures of HDL function. The recently reported association between the Haptoglobin (Hp) 2 allele and CAD incidence in diabetes is also thought, at least partially, to relate to impaired HDL function, i.e. impaired reverse cholesterol transport, in these individuals. Hp is an acute phase plasma protein whose main function is to bind free hemoglobin, thereby inhibiting heme iron release and thus reducing hemoglobin-induced oxidative tissue damage. In T1D, we showed a significantly increased CAD risk with Hp 2-2 and a linear trend toward increased risk with the number of Hp 2 alleles. Additionally, in our HapE intervention study, HDL-mediated cholesterol efflux decreased linearly with the number of Hp 2 alleles, whereas vitamin E improved efflux among Hp 2-2 carriers. Given these data, our aim, using novel sophisticated methods, is to determine: a) whether HDL function (sterol efflux) is impaired in T1D compared to non-diabetic controls (overall and by gender); b) the ability of HDL function to predict CAD in T1D by gender; and c) to what extent HDL function explains the reported Hp- CAD association in T1D. We thus propose to quantify HDL efflux capacity with macrophages using a well- validated assay, and complement these studies with state-of-the art quantification of the concentration/size of HDL particles and HDL's protein cargo (providing information on HDL's anti-inflammatory and anti-oxidative properties). The proteomic analyses, though more exploratory in nature, will provide data on HDL's anti- inflammatory/anti-oxidative properties, which would be of great interest as inflammation/oxidative stress play a role in atherosclerosis development and as Hp is an acute phase protein with anti-oxidative properties. With this research we therefore aim to further our understanding of factors that influence HDL's cardioprotective effects in patients with T1D and shed light on gender differences as well as the mechanisms underlying the increased CAD risk associated with the Hp 2 allele in this population.