Gillenwater Lucas A, Galbraith Matthew D, Rachubinski Angela L, Eduthan Neetha Paul, Sullivan Kelly D, Espinosa Joaquin M, Costello James C
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Sci Adv. 2024 Dec 13;10(50):eadq3073. doi: 10.1126/sciadv.adq3073.
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.
唐氏综合征（DS）由21三体（T21）引起，会导致免疫和代谢失调。与整倍体人群相比，DS患者同时出现多种病症的几率更高。然而，免疫和代谢改变与DS临床表现之间的相互作用仍知之甚少。在此，我们报告了对DS免疫代谢途径的综合分析。利用多组学数据，我们推断了由特定转录程序介导的细胞因子-代谢物关系。与整倍体对照相比，我们观察到DS患者中干扰素反应、血红素代谢和氧化磷酸化相关基因对免疫代谢相互作用的介导作用增强。对DS患者免疫代谢关系进行无监督聚类，发现了同时出现多种病症频率不同的亚组。在各个亚组中，我们观察到DNA修复、刺猬信号通路和血管生成的介导作用存在差异。这种分子分层与DS中观察到的临床异质性相关，表明整合多个组学图谱揭示了DS同时出现多种病症所特有的协同失调轴。
