Down syndrome (DS), caused by trisomy 21 (T21), results in immune and metabolic dysregulation. People with DS experience co-occurring conditions at higher rates than the euploid population. However, the interplay between immune and metabolic alterations and the clinical manifestations of DS are poorly understood. Here, we report an integrated analysis of immunometabolic pathways in DS. Using multi-omics data, we infered cytokine-metabolite relationships mediated by specific transcriptional programs. We observed increased mediation of immunometabolic interactions in those with DS compared to euploid controls by genes in interferon response, heme metabolism, and oxidative phosphorylation. Unsupervised clustering of immunometabolic relationships in people with DS revealed subgroups with different frequencies of co-occurring conditions. Across the subgroups, we observed distinct mediation by DNA repair, Hedgehog signaling, and angiogenesis. The molecular stratification associates with the clinical heterogeneity observed in DS, suggesting that integrating multiple omic profiles reveals axes of coordinated dysregulation specific to DS co-occurring conditions.

中文翻译：

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唐氏综合征免疫代谢相互作用的综合分析


唐氏综合症 （DS） 由 21 三体综合征 （T21） 引起，导致免疫和代谢失调。唐氏综合征患者同时发生病症的几率高于整倍体人群。然而，免疫和代谢改变与 DS 临床表现之间的相互作用知之甚少。在这里，我们报告了 DS 中免疫代谢途径的综合分析。使用多组学数据，我们推断了由特定转录程序介导的细胞因子-代谢物关系。我们观察到 DS 患者与整倍体对照相比，干扰素反应、血红素代谢和氧化磷酸化基因对免疫代谢相互作用的介导增加。DS 患者免疫代谢关系的无监督聚类揭示了具有不同共存病症频率的亚组。在亚组中，我们观察到 DNA 修复、 Hedgehog 信号传导和血管生成的不同介导。分子分层与 DS 中观察到的临床异质性相关，表明整合多个组学特征揭示了特定于 DS 共存病症的协调失调轴。