基于影像组学及基因组学的β-谷固醇血症致心血管早期病变及机制研究

β-sitosterolemia (STSL) is a rare recessive genetic metabolic disease. A series of clinical manifestations were generated by ABCG5/G8 gene mutations, including extreme increases in plasma concentrations of sterols, cutaneous xanthomas, premature atherosclerosis (As), and anemia. The disease is effective with Ezetimibe. Due to clinical manifestation resembles familial hypercholesterolemia, it is often misdiagnosed. It has been recently reported that glucosamine is more prone to be oxidized and pro-inflammatory, and the onset of As is earlier and more severe, but the pathogenesis is unclear. We have collected 10 cases of STSL patients and families with ABCG5/G8 mutations in the previous period. Serum sterols and cholesterol levels were significantly increased, and As was severe. It was concluded that the increase in sterols may be through (1) self-oxidation (2) interference with cholesterol. Both metabolic pathways may cause inflammation and As. This project intends to use imageomics combined with genomics technology to analyze genotypes and early As in STSL patients; to use gas chromatography to detect sterol profiles; to establish ezetimibe in STSL rat models to detect sterol profiles; Ultrasound and PET/CT devices were used to detect cardiovascular structure and function; isolated aortic intima was analyzed for sterol profiles and inflammatory factors; total RNA was extracted from liver tissue for transcriptome sequencing and differentially screened for sterol metabolic pathways and related genes; immunohistochemical validation. The results help reveal the early cardiovascular features and pathogenesis of STSL.

β-谷固醇血症（STSL）是罕见的隐性遗传病，由ABCG5/G8基因突变导致血浆谷固醇极度增高、皮肤黄色瘤、早发动脉粥样硬化（As）及贫血等，依折麦布治疗有效，因临床表现酷似家族性高胆固醇血症而被误诊。新近报道谷固醇更易被氧化促炎性强，As发病更早且严重，但发病机制不清。我们前期已收集10例ABCG5/G8突变的STSL患者及家系，血谷固醇及胆固醇水平均大幅增高，As严重，故推断谷固醇增高可能通过（1）自身易被氧化（2）干扰胆固醇代谢两条途径引发炎症和As。本项目拟应用影像组学结合基因组学技术，分析STSL患者基因型及早期As发生发展，气相色谱检测固醇谱；依折麦布饲喂STSL大鼠模型，小动物专用超声和PET/CT研究心血管结构和功能，分离主动脉内膜检测固醇谱和炎症因子，提取肝组织总RNA转录组测序差异筛选固醇代谢通路及相关基因，免疫组化验证。结果有助于揭示STSL早期心血管病变及发病机制。

β-谷固醇血症（STSL）是罕见的隐性遗传病，由ABCG5/G8基因突变导致血浆谷固醇极度增高、皮肤黄色瘤、早发动脉粥样硬化（As）及贫血等，依折麦布治疗有效，因临床表现与家族性高胆固醇血症相似容易导致误诊。新近报道谷固醇更易被氧化促炎性强，As发病更早且严重，但发病机制不清。β-谷固醇血症是脂质代谢相关的遗传性疾病，患者儿童时期即可发生动脉粥样硬化等心血管病变，尽管导致其心血管病变的机制尚未明确，但现有证据发现体内升高的LDL-C及谷固醇有关。ABCG5患者突变患者的心脏瓣膜损害及动脉粥样硬化等血管损害严重。收集β-谷固醇血症患者及家系成员血清、DNA和临床资料，填写调查问卷，制作家系图，并收集纯合FH患者、杂合FH患者及胆固醇水平正常组作为对照，建立样本资源库。应用多种超声心动图技术分析患者心脏、大血管结构及功能的早期变化，血管应变和应变率超声技术早期评估血管弹性变化，负荷超声冠脉血流显像评估冠状动脉血流储备，二维、三维斑点追踪技术对心肌进行分层应变等生物力学分析,结合SPECT及PET/CT进行多模态影像学研究心肌功能，测量更多低灌注和代谢的定量数据。我们前期已收40例ABCG5/G8突变的STSL患者及家系，血谷固醇及胆固醇水平均大幅增高，As严重，故推断谷固醇增高可能通过（1）自身易被氧化（2）干扰胆固醇代谢两 条途径引发炎症和As。本项目拟应用影像组学结合基因组学技术，分析STSL患者基因型及早期As发生发展，气相色谱检测固醇谱；分离主动脉内膜检测固醇谱和炎症因子，提取肝组织总RNA转录组测序差异筛选固醇代谢通路及相关基因，免疫组化验证。结果有助于揭示STSL早期心血管病变及发病机制。

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