Serum chlorinated lipids as predictors of cardiovascular risk in lupus

血清氯化脂质作为狼疮心血管风险的预测因子

• 批准号: 7897511
• 负责人: DAVID A. FORD
• 金额: $ 22.95万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897511
• 关键词: Acids; Age; Alcohols; Aldehydes; Arterial Fatty Streak; Arts; Atherosclerosis; Autoimmune Diseases; Biochemical; Biological Markers; Blood Vessels; C-reactive protein; Calcium; Cardiovascular Diseases; Cardiovascular system; Clinical; Clinical Data; Consent; Control Groups; Coronary Arteriosclerosis; Coupled; Data; Data Collection; Detection; Development; Diagnosis; Disease; Disease Progression; Epidemiologic Studies; Goals; Health; High Density Lipoproteins; Human; Image; Incidence; Inflammatory; LDL Cholesterol Lipoproteins; Label; Letters; Lipids; Low-Density Lipoproteins; Lupus; Measurement; Measures; Morbidity - disease rate; NIH Program Announcements; Nature; Outcome; Patients; Peroxidases; Plasma; Predictive Value; Research; Risk Assessment; Saints; Sampling; Serum; Shipping; Ships; Son; Specimen; Surrogate Markers; Technology; Testing; Therapeutic; Thick; Translational Research; Ultrasonography; Universities; Woman; X-Ray Computed Tomography; bone; calcification; cardiovascular disorder risk; cardiovascular imaging; cardiovascular risk factor; cohort; coronary artery calcification; improved; in vivo; indexing; intima media; metabolomics; mortality; novel; outcome forecast; oxidation; oxidized low density lipoprotein; public health relevance; response; sex

DESCRIPTION (provided by applicant): Systemic lupus erythrematosus (SLE) is a deadly autoimmune disease with a broad range of clinical manifestations. A leading cause of morbidity and mortality in patients with SLE is cardiovascular disease (CVD). Due to the multifactorial nature of SLE it can be envisaged that a broad panel of biomarkers will be needed to pro- vide biomolecular signatures of the array of clinical manifestations, including increased risk of CVD. We have discovered 1-chlorofatty aldehyde (1-ClFALD) as a novel myeloperoxidase (MPO)-generated lipid oxidation product that is increased 1,400-fold in the vascular wall of human atheromas. Recently we showed that 1-chlo- rofatty acid (1-ClFA) and 1-chlorofatty alcohol (1-ClFOH) are stable metabolites of 1-ClFALD that are present in human serum. Preliminary data suggest that serum levels of the 1-chlorofatty acids, 2-chlorohexadecanoic acid and 2-chlorooctadecanoic acid, are elevated in subjects with SLE compared to a control group of subjects with a similar incidence of CVD. Thus, it is likely that biomarkers of in vivo vascular wall MPO activity may prove to be powerful predictors of active SLE and increased cardiovascular risk in SLE patients. The overall goal of this proposal is to examine the relationship between serum levels of both 1-ClFA, as well as 1- ClFOH, with cardiovascular outcomes in an established longitudinal SLE cohort where the primary data has been collected measuring surrogate imaging markers of CVD. Dr. Rosalind Ramsey-Goldman of Northwestern University will provide us with these human serum samples from the SOLVABLE study. SOLVABLE is a 5-year longitudinal epidemiological study where imaging surrogate markers of CVD have been measured. There are two specific aims for this proposal. Specific Aim 1 will test the hypothesis that serum levels of 1-ClFA and 1-ClFOH are elevated in SLE subjects with CVD. Subclinical CVD has been defined in the SOLVABLE study by surrogate imaging measures of disease (i.e., IMT, PI, CAC and AC). Comparisons of these chlorinated lipids as predictors of CVD will be made between SLE and control subjects. Further comparisons will be made between chlorinated lipids and other potential biomarkers including C-reactive protein, cholesterol, LDL, HDL, and oxidized LDL that have previously been quantified in the SOLVABLE study, as well as MPO, which will be quantified in this study. Specific Aim 2 will test the hypothesis that baseline 1-ClFA and 1-ClFOH levels predict 36 month change in imaging markers of subclinical CVD in SLE subjects. Change will be defined as the difference in measures of surrogate imaging markers between year 3 and baseline. Comparisons of these chlorinated lipids as predictors of CVD progression will be made between SLE and control subjects and will be compared to the available data on other pro-inflammatory biomarkers already measured in these subjects. The availability of the collected samples at Northwestern University coupled with cardiovascular imaging data provides an extraordinary opportunity to identify these chlorinated lipid species as novel bio- markers of CVD in this well-defined group of SLE patients. PUBLIC HEALTH RELEVANCE: Systemic lupus erythrematosus (SLE) is a deadly autoimmune disease with a broad range of clinical manifestations. A leading cause of morbidity and mortality in patients with SLE is cardiovascular disease. The overall goal of this proposal is to examine the relationship between serum levels of chlorinated lipids with previously collected data from SLE subjects where the primary data collection has focused on measuring surrogate imaging markers of cardiovascular disease.

描述（由申请人提供）：全身性狼疮性红血病（SLE）是一种致命的自身免疫性疾病，具有广泛的临床表现。 SLE患者发病率和死亡率的主要原因是心血管疾病（CVD）。由于SLE的多因素性质，因此可以预见，将需要大量的生物标志物来表达一系列临床表现的生物分子特征，包括增加CVD的风险。我们发现1-氯氟醛醛（1-clfald）是一种新型的骨髓氧化酶（MPO）生成的脂质氧化产物，在人动脉瘤的血管壁中增加了1,400倍。最近，我们表明1-促脂肪酸（1-CLFA）和1-氯富特醇（1-CLFOH）是人血清中存在的1-clfald的稳定代谢物。初步数据表明，与具有类似CVD的对照组的受试者相比，患有SLE的受试者的1-氯氟酸酸，2-氯己二核酸和2-氯二十烷基酸的水平升高。因此，体内血管壁MPO活性的生物标志物可能被证明是活跃SLE的有力预测指标，而SLE患者的心血管风险增加可能是有力的预测指标。该提案的总体目标是检查1-CLFA和1-CLFOH的血清水平之间的关系，并在既定的纵向SLE群体中都具有心血管结局，其中已经收集了主要数据，以测量CVD的替代成像标记。西北大学的Rosalind Ramsey-Goldman博士将为我们提供可解决的研究中的这些人类血清样本。可解决的方法是一项为期5年的纵向流行病学研究，其中已经测量了CVD的成像替代标记。该提案有两个具体的目标。具体目标1将检验以下假设：在患有CVD的SLE受试者中，1-CLFA和1-CLFOH的血清水平升高。亚临床CVD已通过替代疾病的替代成像测量（即IMT，PI，CAC和AC）来定义。这些氯化脂质的比较将在SLE和对照对象之间进行CVD的预测指标。将在氯化脂质和其他潜在的生物标志物（包括C反应蛋白，胆固醇，LDL，HDL和氧化的LDL）之间进行进一步的比较，这些LDL先前在可溶解的研究中已被量化，以及MPO，这将在这项研究中进行量化。具体目标2将检验以下假设：基线1-CLFA和1-CLFOH水平可预测SLE受试者亚临床CVD成像标记的36个月变化。变化将定义为3年级和基线之间替代成像标记的度量的差异。这些氯化脂质的比较将在SLE和对照对象之间进行CVD进展的预测指标，并将与已在这些受试者中已经测量过的其他促炎生物标志物的可用数据进行比较。西北大学收集的样品的可用性以及心血管成像数据的可用性提供了一个非凡的机会，可以在这组明确定义的SLE患者中识别出这些氯化脂质物种为CVD的新型生物标志物。 公共卫生相关性：全身性红斑狼疮（SLE）是一种致命的自身免疫性疾病，具有广泛的临床表现。 SLE患者发病率和死亡率的主要原因是心血管疾病。该提案的总体目标是检查氯化脂质的血清水平与先前从SLE受试者收集的数据之间的关系，其中主要数据收集的重点是测量心血管疾病的替代成像标记。