ArticleBMC medicine2023
Metabolic systems approaches update molecular insights of clinical phenotypes and cardiovascular risk in patients with homozygous familial hypercholesterolemia.
Article in BMC medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed, 9 citations in OpenAlex.
- Identification of lipid metabolism-related biomarkers in familial hypercholesterolemia via integrated bioinformatics and machine learning approaches.Journal of cardiothoracic surgery · 2026Article
- Article
- Targeting Lysophosphatidic Acid Ameliorates Dyslipidemia in Familial Hypercholesterolemia.Research (Washington, D.C.) · 2025Article
- Untargeted metabolomics reveals distinct biomarkers and metabolic alterations in familial and non-genetic hypercholesterolemia in Saudi patients.Frontiers in medicine · 2025Article
- Targeting tRNA-Derived Non-Coding RNA Alleviates Diabetes-Induced Visual Impairment through Protecting Retinal Neurovascular Unit.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- A microfluidic coculture model for mapping signaling perturbations and precise drug screening against macrophage-mediated dynamic myocardial injury.Acta pharmaceutica Sinica. B · 2024Article
- Acetyl-L-carnitine ameliorates atherosclerosis in LDLRFrontiers in nutrition · 2024Article
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15 authors at 7 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundHomozygous 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.
methodsTwo 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.
resultsBeyond 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.
conclusionsOur 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.
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