Pro‑inflammatory insulin‑resistant lipid phenotype in down syndrome identified by ¹H‑NMR metabolomics in obesity-matched African‑American children and young adults.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Down Syndrome*/metabolism ; Down Syndrome*/blood ; Down Syndrome*/complications ; Lipids*/blood ; Metabolomics*/methods ; Obesity*/metabolism ; Obesity*/blood ; Obesity*/complications ; Insulin Resistance*; Adolescent ; Child ; Female ; Humans ; Male ; Young Adult ; Black or African American ; Lipid Metabolism ; Magnetic Resonance Spectroscopy ; Phenotype ; Proton Magnetic Resonance Spectroscopy

Down syndrome (DS) is associated with elevated rates of insulin resistance and chronic metabolic disease, yet its detailed metabolic and lipidomic profiles, particularly in pediatric populations, remain poorly defined. To characterize plasma lipid profiles in children and young adults with DS and overweight or obesity, to determine degree of lipid heterogeneity and if the observed dyslipidemia is independent of obesity severity. An extended objective is to search for metabolite features that may differentiate DS from weight‑matched controls. Plasma samples from 12 African‑American participants with DS (age 11-21 years, all overweight or obese) and 513 age‑matched overweight or obese controls were profiled by Nightingale ¹H‑NMR spectroscopy (249 metabolites). Because all participants with DS in our cohort were overweight or obese, we restricted the control group to individuals with comparable weight status to minimize confounding by adiposity. Metabolites were log₂‑transformed and standardized to z-scores. Partial least‑squares discriminant analysis (two components) was followed by k‑means clustering (k = 2). Cluster distributions were compared by χ² test, and metabolite differences between clusters, stratified by obesity class, were assessed using Welch's t‑tests and Benjamini-Hochberg false‑discovery correction. Nine of twelve DS samples (75%) clustered into a dyslipidemic profile (cluster 1), compared to 209 of 513 controls (41%), demonstrating a significant enrichment (p = 0.033). Among controls, cluster assignment showed no association with obesity class. Across all obesity strata, 92 metabolites consistently differed between clusters. Cluster 1 exhibited a distinct lipidomic pattern marked by triglyceride enrichment across the lipoprotein spectrum [from extra-extra-large very-low-density lipoprotein (XXL-VLDL) to high-density lipoprotein (HDL)], elevated remnant cholesterol, increased intermediate-density lipoprotein (IDL) and HDL particle concentrations, and cholesterol-ester-poor, triglyceride-rich HDL particles. Additionally, this cluster showed elevated levels of saturated and monounsaturated fatty acids, alongside a relative depletion of Ω-6 polyunsaturated fatty acids. Together, these features recapitulate a lipid profile associated with insulin resistance and pro-inflammatory metabolic dysfunction. A lipidomic profile characterized by high triglyceride and low cholesterol ester content is highly prevalent among children with DS and overweight or obesity, and present in approximately 40% of overweight or obese controls, irrespective of obesity severity. This insulin-resistant phenotype, independent of adiposity, likely reflects intrinsic alterations in lipid metabolism. The use of the Nightingale ¹H‑NMR offers a scalable and clinically accessible platform for detecting this metabolic signature, offering promise for early risk stratification and precision management of metabolic dysfunction in DS.
(© 2025. The Author(s).)

Declarations. Competing interests: The authors declare no competing interests Ethical approval: This study was approved by the Institutional Review Board (IRB) of the Children’s Hospital of Philadelphia and conducted in accordance with the Declaration of Helsinki, the U.S. Common Rule (45 CFR 46), and all applicable institutional guidelines for pediatric and vulnerable populations. Human participants and personal information are all encrypted to ensure no PHI are included and study participants are de-identified. All human subjects or their proxies provided written informed consent. Consent for publication: All authors have provided consent for publication of the manuscript.

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Keywords: African american; Down syndrome; Dyslipidemia; Inflammatory lipid profile; Insulin resistance; Lipoprotein subclasses; Metabolomics; Obesity

0 (Lipids)

Date Created: 20251126 Date Completed: 20251126 Latest Revision: 20251204

20260130

PMC12657509

10.1038/s41598-025-26217-4

41298583