Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, 100029, China.
BMC Med. 2023 Jul 27;21(1):275. doi: 10.1186/s12916-023-02967-8.
Homozygous familial hypercholesterolemia (HoFH) is an orphan metabolic disease characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C), xanthomas, aortic stenosis, and premature atherosclerotic cardiovascular disease (ASCVD). In addition to LDL-C, studies in experimental models and small clinical populations have suggested that other types of metabolic molecules might also be risk factors responsible for cardiovascular complications in HoFH, but definitive evidence from large-scale human studies is still lacking. Herein, we aimed to comprehensively characterize the metabolic features and risk factors of human HoFH by using metabolic systems strategies.
Two independent multi-center cohorts with a total of 868 individuals were included in the cross-sectional study. First, comprehensive serum metabolome/lipidome-wide analyses were employed to identify the metabolomic patterns for differentiating HoFH patients (n = 184) from heterozygous FH (HeFH, n = 376) and non-FH (n = 100) subjects in the discovery cohort. Then, the metabolomic patterns were verified in the validation cohort with 48 HoFH patients, 110 HeFH patients, and 50 non-FH individuals. Subsequently, correlation/regression analyses were performed to investigate the associations of clinical/metabolic alterations with typical phenotypes of HoFH. In the prospective study, a total of 84 HoFH patients with available follow-up were enrolled from the discovery cohort. Targeted metabolomics, deep proteomics, and random forest approaches were performed to investigate the ASCVD-associated biomarkers in HoFH patients.
Beyond LDL-C, various bioactive metabolites in multiple pathways were discovered and validated for differentiating HoFH from HoFH and non-FH. Our results demonstrated that the inflammation and oxidative stress-related metabolites in the pathways of arachidonic acid and lipoprotein(a) metabolism were independently associated with the prevalence of corneal arcus, xanthomas, and supravalvular/valvular aortic stenosis in HoFH patients. Our results also identified a small marker panel consisting of high-density lipoprotein cholesterol, lipoprotein(a), apolipoprotein A1, and eight proinflammatory and proatherogenic metabolites in the pathways of arachidonic acid, phospholipid, carnitine, and sphingolipid metabolism that exhibited significant performances on predicting first ASCVD events in HoFH patients.
Our findings demonstrate that human HoFH is associated with a variety of metabolic abnormalities and is more complex than previously known. Furthermore, this study provides additional metabolic alterations that hold promise as residual risk factors in HoFH population.
家族性高胆固醇血症（HoFH）是一种孤儿代谢疾病，其特征为极低密度脂蛋白胆固醇（LDL-C）极度升高、黄色瘤、主动脉瓣狭窄和早发动脉粥样硬化性心血管疾病（ASCVD）。除了 LDL-C 之外，实验模型和小临床人群的研究表明，其他类型的代谢分子也可能是 HoFH 心血管并发症的风险因素，但仍缺乏来自大规模人群研究的明确证据。在此，我们旨在通过代谢组学策略全面描述 HoFH 患者的代谢特征和风险因素。
本横断面研究纳入了两个独立的多中心队列，共 868 人。首先，采用全面的血清代谢组学/脂质组学分析，鉴定 HoFH 患者（n=184）与杂合子家族性高胆固醇血症（HeFH，n=376）和非 FH（n=100）患者之间的代谢组学模式。然后，在验证队列中对 48 例 HoFH 患者、110 例 HeFH 患者和 50 例非 FH 个体进行了代谢组学模式验证。随后，进行相关性/回归分析，以探讨临床/代谢改变与 HoFH 典型表型之间的关系。在前瞻性研究中，从发现队列中招募了 84 例有随访数据的 HoFH 患者。采用靶向代谢组学、深度蛋白质组学和随机森林方法，研究 HoFH 患者的 ASCVD 相关生物标志物。
除 LDL-C 外，我们还在多个途径中发现并验证了多种生物活性代谢物，用于区分 HoFH 与 HoFH 和非 FH。研究结果表明，HoFH 患者中，与花生四烯酸和脂蛋白（a）代谢途径相关的炎症和氧化应激相关代谢物与角膜弓、黄色瘤和瓣上/瓣下主动脉瓣狭窄的患病率独立相关。研究结果还确定了一个由高密度脂蛋白胆固醇、脂蛋白（a）、载脂蛋白 A1 和八个与花生四烯酸、磷脂、肉碱和神经酰胺代谢途径相关的促炎和促动脉粥样硬化代谢物组成的小标志物组，该标志物组在预测 HoFH 患者首次 ASCVD 事件方面具有显著性能。
我们的研究结果表明，人类 HoFH 与多种代谢异常相关，比之前已知的更为复杂。此外，该研究提供了其他代谢改变，有望成为 HoFH 人群的残余风险因素。
