Serum chlorinated lipids as predictors of cardiovascular risk in lupus

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。导致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，可以预见，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，包括增加心血管疾病的风险。我们发现1-氯代脂肪醛(1-ClFALD)是髓过氧化物酶(MPO)产生的一种新的脂质氧化产物，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-氯脂肪醇(1-ClFOH)是人体血清中1-ClFALD的稳定代谢产物。初步数据显示，与心血管疾病发生率相似的对照组相比，系统性红斑狼疮患者血清中1-氯脂肪酸、2-氯十六酸和2-氯十八酸水平升高。因此，体内血管壁MPO活性的生物标志物可能被证明是SLE活动期和SLE患者心血管风险增加的有力预测因子。这项建议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水平与心血管结果之间的关系，在该队列中收集了测量心血管疾病替代成像标记物的主要数据。西北大学的Rosalind Ramsey-Goldman博士将为我们提供这些来自可解决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，其中测量了心血管疾病的成像替代标记物。这项提议有两个具体目标。具体目标1将检验有心血管疾病的SLE受试者血清1-ClFA和1-ClFOH水平升高的假设。在可解研究中，通过疾病的替代成像指标(即IMT、PI、CAC和AC)定义了亚临床CVD。这些氯化脂质作为心血管疾病的预测因子，将在系统性红斑狼疮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、低密度脂蛋白、高密度脂蛋白和氧化低密度脂蛋白，以及将在本研究中量化的MPO。特定目标2将检验假设，即基线1-ClFA和1-ClFOH水平可预测SLE受试者亚临床心血管成像标志物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志物测量的差异。对这些氯化脂质作为心血管疾病进展预测因子的比较将在SLE和对照组受试者之间进行，并将与这些受试者中已经测量的其他促炎生物标志物的现有数据进行比较。西北大学收集的样本与心血管成像数据相结合，提供了一个非同寻常的机会，可以在这一明确界定的SLE患者组中将这些氯化脂质物种确定为心血管疾病的新生物标志物。 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。导致系统性红斑狼疮患者发病率和死亡率的主要原因是心血管疾病。这项建议的总体目标是检查血清氯化脂质水平与之前从SLE受试者收集的数据之间的关系，其中主要数据收集集中在测量心血管疾病的替代成像标志物上。

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.