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首页> 外文期刊>Current Metabolomics >~1H NMR-Linked Urinary Metabolic Profiling of Niemann-Pick Class Cl (NPC1) Disease: Identification of Potential New Biomarkers using Correlated Component Regression (CCR) and Genetic Algorithm (GA) Analysis Strategies
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~1H NMR-Linked Urinary Metabolic Profiling of Niemann-Pick Class Cl (NPC1) Disease: Identification of Potential New Biomarkers using Correlated Component Regression (CCR) and Genetic Algorithm (GA) Analysis Strategies

机译：Niemann-Pick C1类（NPC1）疾病的〜1H NMR关联的尿代谢谱分析：使用相关分量回归（CCR）和遗传算法（GA）分析策略鉴定潜在的新生物标记

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Niemann-Pick Class 1 (NPC1) disease is a rare, debilitating neurodegenerative lysozomal storage disease; however, urinary biomarkers available for it and its prognosis are currently limited. In order to identify and establish such biomarkers, we employed high-resolution ~1H NMR analysis coupled to a range of multivariate (MV) analysis approaches, i.e. PLS-DA, RFs and uniquely the cross-validated correlated component regression (CCR) strategy in order to discern differences between the urinary metabolic profiles of 13 untreated NPC1 disease and 47 heterozygous (parental) carrier control participants. Novel computational intelligence techniques (CITs) were also employed for this purpose. These ~1H NMR-linked metabolomics analyses revealed significantly elevated urinary excretions of bile acids, branched-chain amino acids (BCAAs) and their intermediates and degradation products [particularly 3-aminoisobutyrate (3-AIB)], glu-tamine, 3-methylhistidine, creatine, quinolinate, succinate and trimethylamine, together with diminished concentrations of nicotinate, iV-methylnicotinamide, N-methyl-2-pyridone-5-carboxamide (2PY), iV-methyl-4-pyridone-5-carboxamide (4PY), and especially trigonelline in NPC1 patients. The CCR and GA designs employed both achieved high levels of classification success, the latter at rates of 96-99%. These results provided evidence for disease-mediated imbalances in enzymes involved in bile acid biosynthesis, BCAA degradation and pyrimidine (thymine) catabolism, together with the nicotinate and nicotinamide, and methylamine metabolism pathways. Metabolite set enrichment and pathway topological analyses indicated that the brain, lysosome, liver, endoplasmic reticulum and mitochondria represented key organ, tissue and sub-cellular localisations for this disease process, observations consistent with NPC1 disease pathology. It is proposed that the BCAA and thymine catabolite 3-AIB, and also selected bile acids, may serve as valuable urinary biomarkers for NPC1 disease.
机译：尼曼-皮克1类（NPC1）疾病是一种罕见的，使人衰弱的神经退行性溶酶体贮积病。然而，目前可用的尿液生物标志物及其预后是有限的。为了鉴定和建立此类生物标志物，我们采用了高分辨率〜1H NMR分析，并结合了多种多变量（MV）分析方法，即PLS-DA，RF和交叉验证的相关成分回归（CCR）策略。为了辨别13例未经治疗的NPC1疾病和47例杂合（父母）携带者对照参与者的尿代谢谱之间的差异。新型计算智能技术（CIT）也用于此目的。这些〜1H NMR关联的代谢组学分析表明，胆汁酸，支链氨基酸（BCAAs）及其中间体和降解产物[特别是3-氨基异丁酸酯（3-AIB）]，谷氨酰胺，3-甲基组氨酸的尿排泄量显着升高，肌酸，喹啉酸酯，琥珀酸酯和三甲胺，以及烟酸酯，iV-甲基烟酰胺，N-甲基-2-吡啶酮-5-甲酰胺（2PY），iV-甲基-4-吡啶酮-5-甲酰胺（4PY）的浓度降低，尤其是NPC1患者中的曲安奈林。使用的CCR和GA设计均实现了很高的分类成功率，后者的分类率为96-99％。这些结果提供了与胆汁酸生物合成，BCAA降解和嘧啶（胸腺嘧啶）分解代谢以及烟酸和烟酰胺以及甲胺代谢途径有关的酶介导的疾病介导的失衡的证据。代谢物的富集和途径拓扑分析表明，脑，溶酶体，肝脏，内质网和线粒体代表了该疾病过程的关键器官，组织和亚细胞定位，与NPC1疾病病理学一致。有人提出，BCAA和胸腺嘧啶分解代谢物3-AIB，以及一些胆汁酸，可以作为NPC1疾病的有价值的尿液生物标志物。

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