Serum chlorinated lipids as predictors of cardiovascular risk in lupus

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种具有广泛临床表现的致死性自身免疫性疾病。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，包括心血管疾病风险增加。我们发现1-氯脂肪醛（1-ClFALD）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1400倍。最近我们发现，1-氯脂肪酸（1-ClFA）和1-氯脂肪酸醇（1-ClFOH）是存在于人血清中的1-氯脂肪酸的稳定代谢物。初步数据表明，与心血管疾病发生率相似的对照组相比，SLE患者血清中1-氯脂肪酸、2-氯十六酸和2-氯十八酸的水平升高。因此，体内血管壁MPO活性的生物标志物可能被证明是SLE活动性和SLE患者心血管风险增加的有力预测因子。本研究的总体目标是研究血清1- clfa和1- ClFOH水平与系统性红斑狼疮纵向队列心血管结局之间的关系，该队列的主要数据收集于测量CVD的替代成像标志物。西北大学的罗莎琳德·拉姆齐-戈德曼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，测量了心血管疾病的影像学替代标志物。这项提议有两个具体目标。特异性目的1将检验SLE合并CVD患者血清中1- clfa和1- clfoh水平升高的假设。在SOLVABLE研究中，亚临床CVD已被定义为疾病的替代影像学指标（即IMT、PI、CAC和AC）。这些氯代脂质作为CVD的预测因子将在SLE和对照组之间进行比较。将进一步比较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LDL，这些在SOLVABLE研究中已经被量化，以及MPO，这将在本研究中被量化。特异性目标2将验证基线1-ClFA和1-ClFOH水平预测SLE患者亚临床CVD影像学标志物36个月变化的假设。变化将被定义为第3年与基线之间替代成像标志物测量的差异。这些氯化脂质作为CVD进展的预测因子将在SLE和对照组受试者之间进行比较，并将与这些受试者中已经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患者中确定这些氯化脂类作为CVD的新型生物标志物。

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.