MicroRNA and metabolomics signatures for adrenomyeloneuropathy disease severity.
MicroRNA and metabolomics signatures for adrenomyeloneuropathy disease severity.
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DOI：
10.1002/jmd2.12323
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发表时间：
2022-11
期刊：
影响因子：
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通讯作者：
Singh, Jaspreet
中科院分区：
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作者：
Turk, Bela Rui;Poisson, Laila Marie;Nemeth, Christina Linnea;Goodman, Jordan;Moser, Ann B;Jones, Richard Owen;Fatemi, Ali;Singh, Jaspreet
肾上腺髓神经病变（AMN）是一种缓慢进展型的肾上腺白质营养不良（ALD），目前尚无临床血浆生物标志物可用于疾病进展。这项可行性研究旨在确定血浆中的代谢组学和微RNA是否为AMN疾病严重程度提供了潜在的生物标志物来源。对AMN和健康人血浆进行代谢组学和RNA测序。使用聚类、京都基因与基因组百科全书（KEGG）途径分析和患者临床扩展残疾状态评分（EDSS）回归进行生物标志物发现和途径分析。对14例AMN和6例健康对照进行分析。AMN显示出强烈的疾病严重程度特异性代谢和miRNA聚类特征。7‐α‐羟基‐3‐氧‐4‐胆甾醇酸酯（7‐HOCA） （r2 = 0.83, p < 0.00001）、硫酸脱氢表雄酮（DHEA‐S; r2 = 0.82, p < 0.00001）、次黄嘌呤（r2 = 0.82, p < 0.00001）以及miRNA‐432‐5p （r2 = 0.68, p < 0.00001）具有很强的、显著的临床相关性。KEGG途径比较轻度和重度疾病确定影响下游系统：GAREM， IGF - 1， CALCRL, SMAD2&3，谷胱甘肽过氧化物酶，LDH和NOS。该可行性研究表明，miRNA和代谢组学是AMN疾病严重程度的潜在血浆生物标志物的来源，既提供疾病特征，也提供具有强临床相关性的个体标志物。受影响系统的网络分析涉及血管、炎症和氧化应激途径的差异改变，提示疾病严重程度特异性机制作为疾病严重程度的功能。
Adrenomyeloneuropathy (AMN), the slow progressive phenotype of adrenoleukodystrophy (ALD), has no clinical plasma biomarker for disease progression. This feasibility study aimed to determine whether metabolomics and micro‐RNA in blood plasma provide a potential source of biomarkers for AMN disease severity. Metabolomics and RNA‐seq were performed on AMN and healthy human blood plasma. Biomarker discovery and pathway analyses were performed using clustering, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and regression against patient's clinical Expanded Disability Status Score (EDSS). Fourteen AMN and six healthy control samples were analyzed. AMN showed strong disease‐severity‐specific metabolic and miRNA clustering signatures. Strong, significant clinical correlations were shown for 7‐alpha‐hydroxy‐3‐oxo‐4‐cholestenoate (7‐HOCA) (r 2 = 0.83, p < 0.00001), dehydroepiandrosterone sulfate (DHEA‐S; r 2 = 0.82, p < 0.00001), hypoxanthine (r 2 = 0.82, p < 0.00001), as well as miRNA‐432‐5p (r 2 = 0.68, p < 0.00001). KEGG pathway comparison of mild versus severe disease identified affected downstream systems: GAREM, IGF‐1, CALCRL, SMAD2&3, glutathione peroxidase, LDH, and NOS. This feasibility study demonstrates that miRNA and metabolomics are a source of potential plasma biomarkers for disease severity in AMN, providing both a disease signature and individual markers with strong clinical correlations. Network analyses of affected systems implicate differentially altered vascular, inflammatory, and oxidative stress pathways, suggesting disease‐severity‐specific mechanisms as a function of disease severity.