载脂蛋白-B:A1 比值升高可预测青少年起病的系统性红斑狼疮患者的心血管代谢风险。
Increased apolipoprotein-B:A1 ratio predicts cardiometabolic risk in patients with juvenile onset SLE.
机构信息
Centre for Rheumatology Research, Department of Medicine, University College London, Rayne Building, London W1CE 6JF, UK; Centre for Adolescent Rheumatology Versus Arthritis, Department of Medicine, University College London, Rayne Building, London W1CE 6JF, UK.
Centre for Rheumatology Research, Department of Medicine, University College London, Rayne Building, London W1CE 6JF, UK; Centre for Cardiometabolic and Vascular Science, Department of Medicine, University College London, London W1CE 6JF, UK.
出版信息
EBioMedicine. 2021 Mar;65:103243. doi: 10.1016/j.ebiom.2021.103243. Epub 2021 Feb 24.
BACKGROUND
Cardiovascular disease is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE). Traditional factors for cardiovascular risk (CVR) prediction are less robust in younger patients. More reliable CVR biomarkers are needed for JSLE patient stratification and to identify therapeutic approaches to reduce cardiovascular morbidity and mortality in JSLE.
METHODS
Serum metabolomic analysis (including >200 lipoprotein measures) was performed on a discovery (n=31, median age 19) and validation (n=31, median age 19) cohort of JSLE patients. Data was analysed using cluster, receiver operating characteristic analysis and logistic regression. RNA-sequencing assessed gene expression in matched patient samples.
FINDINGS
Hierarchical clustering of lipoprotein measures identified and validated two unique JSLE groups. Group-1 had an atherogenic and Group-2 had an atheroprotective lipoprotien profile. Apolipoprotein(Apo)B:ApoA1 distinguished the two groups with high specificity (96.2%) and sensitivity (96.7%). JSLE patients with high ApoB:ApoA1 ratio had increased CD8+ T-cell frequencies and a CD8+ T-cell transcriptomic profile enriched in genes associated with atherogenic processes including interferon signaling. These metabolic and immune signatures overlapped statistically significantly with lipid biomarkers associated with sub-clinical atherosclerosis in adult SLE patients and with genes overexpressed in T-cells from human atherosclerotic plaque respectively. Finally, baseline ApoB:ApoA1 ratio correlated positively with SLE disease activity index (r=0.43, p=0.0009) and negatively with Lupus Low Disease Activity State (r=-0.43, p=0.0009) over 5-year follow-up.
INTERPRETATION
Multi-omic analysis identified high ApoB:ApoA1 as a potential biomarker of increased cardiometabolic risk and worse clinical outcomes in JSLE. ApoB:ApoA1 could help identify patients that require increased disease monitoring, lipid modification or lifestyle changes.
FUNDING
Lupus UK, The Rosetrees Trust, British Heart Foundation, UCL & Birkbeck MRC Doctoral Training Programme and Versus Arthritis.
背景
心血管疾病是青少年起病系统性红斑狼疮（JSLE）患者死亡的主要原因。心血管风险（CVR）预测的传统因素在年轻患者中不太可靠。需要更可靠的 CVR 生物标志物来对 JSLE 患者进行分层，并确定治疗方法以降低 JSLE 患者的心血管发病率和死亡率。
方法
对 31 名（中位年龄 19 岁）JSLE 患者的发现队列和 31 名（中位年龄 19 岁）验证队列进行了血清代谢组学分析（包括>200 种脂蛋白测量）。使用聚类、接受者操作特征分析和逻辑回归对数据进行分析。RNA 测序评估了匹配患者样本中的基因表达。
结果
脂蛋白测量的层次聚类确定并验证了两个独特的 JSLE 组。第 1 组具有动脉粥样硬化性，第 2 组具有动脉保护脂蛋白谱。载脂蛋白（Apo）B:ApoA1 可区分这两组，具有高特异性（96.2%）和敏感性（96.7%）。ApoB:ApoA1 比值高的 JSLE 患者 CD8+T 细胞频率增加，CD8+T 细胞转录组谱富含与动脉粥样硬化过程相关的基因，包括干扰素信号。这些代谢和免疫特征与成人 SLE 患者亚临床动脉粥样硬化相关的脂质生物标志物以及人类动脉粥样硬化斑块中过度表达的基因在统计学上显著重叠。最后，基线 ApoB:ApoA1 比值与 SLE 疾病活动指数呈正相关（r=0.43，p=0.0009），与 5 年随访期间的狼疮低疾病活动状态呈负相关（r=-0.43，p=0.0009）。
解释
多组学分析确定高 ApoB:ApoA1 是 JSLE 患者代谢风险增加和临床结局恶化的潜在生物标志物。ApoB:ApoA1 可帮助识别需要增加疾病监测、脂质修饰或生活方式改变的患者。
资金
狼疮英国、罗斯特里基金会、英国心脏基金会、UCL 和 Birkbeck 医学研究委员会博士培训计划以及对抗关节炎。
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