罕见病研究2024，Vol.3Issue(1) ：42-49.DOI:10.12376/j.issn.2097-0501.2024.01.006

液相色谱-串联质谱检测法布雷病患者血浆Lyso-GL3水平及其与临床型-基因型关联分析

Using Liquid Chromatography-Tandem Mass Spectrometry in Detecting Plasma Lyso-GL3 Levels in Patients with Fabry Disease and the Association Analysis of Phenotype-Genotype of the Disease

欧阳彦 陈冰 潘晓霞 任红 谢静远 王朝晖 李晓 王伟铭 俞夏莲 杨俪 陈楠
罕见病研究2024，Vol.3Issue(1) ：42-49.DOI:10.12376/j.issn.2097-0501.2024.01.006
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液相色谱-串联质谱检测法布雷病患者血浆Lyso-GL3水平及其与临床型-基因型关联分析

Using Liquid Chromatography-Tandem Mass Spectrometry in Detecting Plasma Lyso-GL3 Levels in Patients with Fabry Disease and the Association Analysis of Phenotype-Genotype of the Disease

欧阳彦 1陈冰 2潘晓霞 1任红 1谢静远 1王朝晖 1李晓 1王伟铭 1俞夏莲 1杨俪 1陈楠1
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作者信息

  • 1. 上海交通大学医学院附属瑞金医院肾脏科上海交通大学医学院肾脏病研究所,上海 200025
  • 2. 上海交通大学医学院附属瑞金医院药剂科,上海 200025
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摘要

目的 应用液相色谱-串联质谱(LC-MS/MS),测定法布雷病患者血浆Lyso-GL3 水平,分析其与肾脏损害之间的相关性.方法 纳入基因诊断明确的法布雷病患者39 例,用LC-MS/MS分析方法检测Lyso-GL3 的血浆水平,并获取患者详细临床信息,包括α-半乳糖苷酶A活性、基因变异、尿蛋白定量、平均动脉压及估算肾小球滤过率,统计分析Lyso-GL3在不同临床表型、基因型中的水平差异,以及与临床指标的关联.结果 Lyso-GL3 在 0.7856～400 ng/mL内线性良好.进一步分析上海交通大学医学院附属瑞金医院确诊的39 例法布雷病患者,Lyso-GL3 水平中位值为23.6 ng/mL(4.3～92.9 ng/mL);经典型患者血浆Lyso-GL3水平显著高于迟发型患者(中位值90.0 ng/mL vs.3.9 ng/mL,P＜0.0001).无论移码突变及剪切突变,还是无义突变患者的Lyso-GL3 水平,均显著高于错义突变患者(分别为中位值 119.7 ng/mL vs.11.9 ng/mL,P=0.006,中位值97.0 ng/mL vs.11.9 ng/mL,P=0.015).而关联分析发现,Lyso-GL3 与24h尿蛋白定量、平均动脉压及估算肾小球滤过率均无显著关联.结论 应用LC-MS/MS对血浆Lyso-GL3进行定量检测发现,在不同临床表型之间Lyso-GL3水平有差异,提示血浆Lyso-GL3 有助于进行临床分型.但不同的基因型之间,Lyso-GL3 水平仍有重合,且Lyso-GL3与肾脏临床指标无显著的线性相关,提示临床亟需更为精准评估法布雷病患者肾脏受累及预后的工具.

Abstract

Objective Using the liquid chromatography-tandem mass spectrometry(LC-MS/MS)to determine the plasma level of Lyso-GL3 in patients with Fabry disease and to analyze the clinical application of the method.Methods Thirty-nine patients with a genetic diagnosis of Fabry disease were included,and plasma levels of Lyso-GL3 were measured by LC-MS/MS analysis,and detailed clinical information of the patients was obtained including:α-galactosidase A activity,genetic variants,quantification of urine protein,mean arterial pressure,and estimation of glomerular filtration rate,and the differences in the levels of Lyso-GL3 in different clinical phenotypes and genotypes were statistically analyzed,as well as the association with clinical indicators.Results Lyso-GL3 showed good linearity within 0.7856-400 ng/mL(r=0.9992).Further analysis of 39 Fabry disease patients diagnosed in Ruijin Hospital,Shanghai Jiao Tong University School of Medicine showed a median Lyso-GL3 concentration of 23.6 ng/mL(4.3-92.9 ng/mL);Lyso-GL3 levels were significantly higher in patients with both the frameshift and the splicing mutations,as well as in patients with the nonsense mutations,than in patients with the missense mutations(median value 119.7 ng/mL vs.11.9 ng/mL,P=0.006,and medi-an value 97.0 ng/mL vs.11.9 ng/mL,P=0.015,respectively).Whereas,association analysis revealed that Ly-so-GL3 was not significantly associated with urinary protein,mean arterial pressure and estimated glomerular fil-tration rate.Conclusions The using of LC-MS/MS to quantify plasma Lyso-GL showed significant differences in Lyso-GL3 concentrations between classical and atypical phenotypes,suggesting that plasma Lyso-GL3 may help with clinical phenotypes.However,Lyso-GL3 levels is found to be overlapped between genotypes.No significant linear correlation was found between Lyso-GL3 and renal clinical indicators,suggesting the urgent need in finding a more accurate tool to assess renal involvement and prognosis in patients with Fabry disease.

关键词

法布雷病/血浆Lyso-GL3/液相色谱-串联质谱

Key words

Fabry disease/plasma Lyso-GL3/liquid chromatography-tandem mass spectrometry

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基金项目

国家自然科学基金(82270739)

国家自然科学基金(81900656)

国家自然科学基金(81870460)

国家自然科学基金(81570598)

国家自然科学基金(81370015)

上海市"医苑新星"青年医学人才培养资助计划(沪卫人事[2023]62号)

上海交通大学"交大之星"计划医工交叉研究基金青年项目(YG2019QNA37)

上海交通大学"交大之星"计划医工交叉研究基金青年项目(YG2019ZDA18)

Shanghai'Rising Star of Medical Talent'Youth Development Program(SHWSRS2023_62)

出版年

2024
罕见病研究

罕见病研究

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