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）：系统性红斑狼疮（SLE）是一种致命的自身免疫性疾病，具有广泛的临床表现。 SLE 患者发病和死亡的主要原因是心血管疾病 (CVD)。由于 SLE 的多因素性质，可以预见，将需要广泛的生物标志物来提供一系列临床表现的生物分子特征，包括 CVD 风险增加。我们发现 1-氯脂肪醛 (1-ClFALD) 是一种新型髓过氧化物酶 (MPO) 生成的脂质氧化产物，其在人类动脉粥样硬化斑块的血管壁中增加了 1,400 倍。最近我们发现 1-氯脂肪酸 (1-ClFA) 和 1-氯脂肪醇 (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CVD发病率相似的对照组受试者相比，SLE受试者中1-氯脂肪酸、2-氯十六烷酸和2-氯十八烷酸的血清水平升高。因此，体内血管壁 MPO 活性的生物标志物可能被证明是活动性 SLE 和 SLE 患者心血管风险增加的有力预测因子。该提案的总体目标是在已建立的纵向 SLE 队列中检查 1-ClFA 和 1-ClFOH 的血清水平与心血管结局之间的关系，其中已收集测量 CVD 替代成像标记物的主要数据。西北大学的 Rosalind Ramsey-Goldman 博士将为我们提供来自 SOLVABLE 研究的人类血清样本。 SOLVABLE 是一项为期 5 年的纵向流行病学研究，其中测量了 CVD 的影像替代标志物。该提案有两个具体目标。具体目标 1 将检验以下假设：患有 CVD 的 SLE 受试者中 1-ClFA 和 1-ClFOH 的血清水平升高。 SOLVABLE 研究中通过疾病的替代影像学测量（即 IMT、PI、CAC 和 AC）定义了亚临床 CVD。将在 SLE 和对照受试者之间对这些氯化脂质作为 CVD 预测因子进行比较。将在氯化脂质和其他潜在生物标志物之间进行进一步比较，包括 C 反应蛋白、胆固醇、LDL、HDL 和氧化 LDL（先前已在 SOLVABLE 研究中定量）以及 MPO（将在本研究中定量）。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 影像标志物 36 个月的变化。变化将被定义为第 3 年和基线之间替代成像标记物测量的差异。将在 SLE 受试者和对照受试者之间对这些氯化脂质作为 CVD 进展的预测因子进行比较，并将与已在这些受试者中测量的其他促炎生物标志物的可用数据进行比较。西北大学收集的样本与心血管成像数据相结合，提供了一个绝佳的机会，可以将这些氯化脂质物种识别为这一明确定义的 SLE 患者群体中 CVD 的新生物标志物。 公众健康相关性：系统性红斑狼疮 (SLE) 是一种致命的自身免疫性疾病，具有广泛的临床表现。 SLE 患者发病和死亡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之前从 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物。