Urinary Globotriaosylsphingosine-Related Biomarkers for Fabry Disease Targeted by Metabolomics
Urinary Globotriaosylsphingosine-Related Biomarkers for Fabry Disease Targeted by Metabolomics
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DOI：
10.1021/ac203433e
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发表时间：
2012-03-20
影响因子：
7.4
通讯作者：
Clarke, Joe T. R.
中科院分区：
文献类型：
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作者：
Auray-Blais, Christiane;Boutin, Michel;Clarke, Joe T. R.
法布里病是一种由α -半乳糖苷酶a缺乏引起的溶酶体贮积障碍，导致鞘糖脂在器官和组织中积聚，包括血浆和尿液。两种疾病特异性的Fabry生物标志物已经在血浆和尿液中被鉴定和量化：globotriaosylneuroide （Gb(3)）和globotriaosylsphingosin （lyso-Gb(3)）。研究人员仍在继续寻找可能作为疾病严重程度和治疗反应可靠指标的生物标志物。本研究的主要目的是利用飞行时间质谱代谢组学方法靶向其他尿液生物标志物。分析63例未经治疗的Fabry患者和59例对照者的尿液代谢物。对一组男性样本进行的多变量统计分析显示，尿液中有七种新的法布里生物标志物，所有溶索- gb(3)类似物都具有修饰的鞘氨醇部分。通过精确的质量测量（- C2H4, - C2H4 + O, - H-2, - H-2 + O, + O, + H2O2, + H2O3）确定了鞘氨醇改性的经验公式。我们通过测量所有Fabry患者中每种类似物的面积计数来评估lyso-Gb(3)及其七种类似物的相对浓度。所有样本归一化为肌酐。我们发现患有法布里病的男性比女性浓度更高。在对照组中没有检测到这些生物标志物。据我们所知，这是首次在尿液中检测到lyso-Gb(3)相关的法布里病生物标志物。
Fabry disease is a lysosomal storage disorder caused by deficiency of alpha-galactosidase A, resulting in glycosphingolipid accumulation in organs and tissues, including plasma and urine. Two disease-specific Fabry biomarkers have been identified and quantified in plasma and urine: globotriaosylceramide (Gb(3)) and globotriaosylsphingosine (lyso-Gb(3)). The search continues for biomarkers that might be reliable indicators of disease severity and response to treatment. The main objective of this study was to target other urinary biomarkers using a time-of-flight mass spectrometry metabolomic approach. Urinary metabolites of 63 untreated Fabry patients and 59 controls were analyzed. A multivariate statistical analysis performed on a subset of male samples revealed seven novel Fabry biomarkers in urine, all lyso-Gb(3) analogues having modified sphingosine moieties. The empirical formulas of the sphingosine modifications were determined by exact mass measurements (- C2H4, - C2H4 + O, - H-2, - H-2 + O, + O, + H2O2, + H2O3). We evaluated the relative concentration of lyso-Gb(3) and its seven analogues by measuring area counts for each analogue in all Fabry patients. All samples were normalized to creatinine. We found higher concentrations for males with Fabry disease compared to females. None of these biomarkers were detected in controls. To our knowledge, this is the first time that lyso-Gb(3)-related Fabry disease biomarkers are detected in urine.