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（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，可以设想将需要一组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-ClOID）是一种新的髓过氧化物酶（MPO）产生的脂质氧化产物，在人类动脉粥样硬化的血管壁中增加了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1-ClODN在人血清中的稳定代谢产物。初步数据表明，与具有类似CVD发病率的对照组受试者相比，患有SLE的受试者中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队列中检查血清1-ClFA和1- ClFOH水平与心血管结局之间的关系，其中收集了测量CVD替代成像标志物的主要数据。西北大学的Rosalind Ramsey-Goldman博士将为我们提供这些来自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的成像替代标志物。这项建议有两个具体目标。具体目标1将检验患有CVD的SLE受试者中1-ClFA和1-ClFOH的血清水平升高的假设。在SOLVABLE研究中，亚临床CVD已通过疾病的替代成像指标（即，IMT、PI、CAC和AC）。将在SLE和对照受试者之间比较这些氯化脂质作为CVD的预测因子。将进一步比较氯化脂质和其他潜在生物标志物，包括先前在SOLVABLE研究中定量的C反应蛋白、胆固醇、LDL、HDL和氧化LDL，以及将在本研究中定量的MPO。具体目标2将检验以下假设：基线1-ClFA和1-ClFOH水平预测SLE受试者亚临床CVD的成像标志物的36个月变化。变化将定义为第3年与基线之间替代成像标志物测量值的差异。将在SLE和对照受试者之间比较这些氯化脂质作为CVD进展的预测因子，并将其与这些受试者中已测量的其他促炎生物标志物的可用数据进行比较。在西北大学收集的样本的可用性加上心血管成像数据提供了一个非凡的机会，以确定这些氯化脂质物质作为这个明确定义的SLE患者组中CVD的新生物标志物。 公共卫生相关性：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血清氯化脂质水平与先前从SLE受试者收集的数据之间的关系，其中主要数据收集集中于测量心血管疾病的替代成像标志物。