CN106053615A - 人类眼部的生物标记及其方法 - Google Patents
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Abstract
本发明提供一种侦测及诊断人类眼部的息肉状脉络膜血管病变的生物标记，包括确定高同型半胱胺酸血症的作用程度，其中，该高同型半胱胺酸血症的作用程度与该人类眼部的息肉状脉络膜血管病变高度相关联。此外，本发明进一步提供一种侦测及诊断人类眼部的息肉状脉络膜血管病变的方法。
Description
技术领域
本发明涉及关于息肉状脉络膜血管病变(polypoidal choroidalvasculopathy，PCV)的侦测、预测及诊断，尤指基于高同型半胱胺酸血症(Hyperhomocysteinemia)的作用程度侦测人类眼部的息肉状脉络膜血管病变。
背景技术
眼部息肉状脉络膜血管病变(polypoidal choroidal vasculopathy，PCV)是造成失明常见的病因，由于这类的新生血管较为脆弱，较容易破裂出血以及营养供应不良，且容易造成感光细胞的萎缩及死亡。
现今，医生诊断该病变最有效的方式是利用眼底循血绿血管摄影(indocyanine green angiography，ICGA)，藉由影像的高荧光的区域，且根据其他伴随的病症或在低荧光光晕及前五分钟急遽从暗变亮上的亮度变化，来诊断息肉状脉络膜血管病变的位置。
再者，老年性黄斑部病变(age-related macular degeneration，AMD)在亚洲是造成老年失明的常见病症，其中老年性黄斑部病变可分为干性(dry，early)及湿性(wet，late)，干性老年性黄斑部病变在视网膜色素上皮层(retinalpigment epithelium，RPE)上长出脉络膜玻璃膜疣(drusen)或地图状萎缩(geographic atrophy)，进而慢性地导致视力衰退，湿性老年性黄斑部病变则由于脉络膜新生血管(choroidal neovascularization，CNV)，容易造成血管破裂出血及养分供应不够，进而造成视网膜破坏，所以会损害视网膜视觉中心而失明，以及形成视网膜破洞。因此，老年性黄斑部病变的罹病原因一般与年龄老化、抽烟、喝酒、糖尿病、高血压、基因及曝露于蓝光有关。
高半胱胺酸(homocysteine)是蛋胺酸的代谢过程中产生的天然存在的含硫氨基酸。高半胱胺酸的高血浆程度已被确定为血管疾病的危险因子，如心血管疾病及中风、老年痴呆症及阿尔茨海默氏病症。在患者具有视网膜血管闭塞性疾病、假性青光眼及糖尿病性视网膜疾病中亦可观察到升高的血浆高半胱胺酸的程度。同样地，在具有老年性黄斑部病变的患者中也可观察到升高的血浆高半胱胺酸的程度。
C-反应蛋白(C-reactive protein，CRP)是一种全身性炎症的生物标记以及心血管疾病的一个危险因素。日本研究人员研究发现升高的高敏感度C反应蛋白(high sensitivity C-reactive protein，hsCRP)的程度与息肉状脉络膜血管病变有显著的关联，且得出炎症过程参与息肉状脉络膜血管病变的发病机制的结论。
因此，如何进一步阐明及证实息肉状脉络膜血管病变与血管疾病的危险因素有关，实为目前各界亟欲解决的技术问题。
发明内容
鉴于上述现有技术的缺点，本发明提供一种侦测或诊断人类眼部的息肉状脉络膜血管病变(polypoidal choroidal vasculopathy，PCV)的生物标记，包括：确定高同型半胱胺酸血症(Hyperhomocysteinemia)的作用程度，其中，该高同型半胱胺酸血症的作用程度与该人类眼部的息肉状脉络膜血管病变高度相关联。
再者，本发明进一步提供一种侦测或诊断人类眼部的息肉状脉络膜血管病变的方法，包括以下步骤：确定从该人类眼部取得的多个生物样品的高同型半胱胺酸血症的作用程度；以及将该高同型半胱胺酸血症的作用程度与高同型半胱胺酸血症的作用对照程度比较，其中，该高同型半胱胺酸血症的作用程度与该人类眼部的息肉状脉络膜血管病变高度相关联。
较佳地，该多个生物样品的数据可包括年龄、性别、生活方式因素、吸烟、饮酒量、用药史、高血压病史、糖尿病病史、冠状动脉疾病病史、脑血管疾病病史，但本发明不限于此。
较佳地，该高同型半胱胺酸血症的作用程度可藉由以下分析方法确定：总血浆高半胱胺酸分析(total plasma homocysteine analysis)、高敏感度C反应蛋白分析(high sensitivity C-reactive protein(hsCRP)analysis)及统计分析，但本发明不限于此。
较佳地，该统计分析使用多变量逻辑回归模型(multivariable logisticregression model)判断血浆高半胱胺酸及高敏感度C反应蛋白的作用程度与该息肉状脉络膜血管病变的关联性。
较佳地，本发明的侦测或诊断人类眼部的息肉状脉络膜血管病变的方法还包括以下步骤：对该人类眼部进行最佳矫正视力检查(best-corrected visualacuity examination)、裂隙灯生物显微镜检查(slit lamp biomicroscopyexamination)及眼底镜检查(fundoscopy examination)。
具体实施方式
以下藉由特定的具体实施例说明本发明的实施方式，熟悉本领域的技术人员可由本说明书所揭示的内容轻易地了解本发明的其他优点及功效。本发明亦可藉由其他不同的具体实例加以施行或应用，本发明说明书中的各项细节亦可基于不同观点与应用在不悖离本发明的精神下进行各种修饰与变更。
以下依据本发明的实施例，描述本发明的侦测及诊断人类眼部的息肉状脉络膜血管病变(polypoidal choroidal vasculopathy，PCV)的生物标记。
研究对象
在本发明的实施例中，确诊为PCV的患者将进行研究。除了老年性黄斑部病变(age-related macular degeneration，AMD)、视网膜血管病变、糖尿病性视网膜病变或青光眼，对照组(control group)可包括接受常规身体检查或后续的疾病，然后每一情况的年龄和性别与对照组相匹配。其中所有研究对象为中华民族患者。
在本发明的实施例中，所有参与者均接受完整的眼科检查，其中包括最佳矫正视力检查(best-corrected acuity examination)、裂隙灯生物显微镜检查(slit lamp biomicroscopy examination)及眼底镜检查(fundoscopyexamination)。再者，在本发明的实施例中，本发明通过瞳孔放大，使用眼底照相机(CF-60UD，佳能公司，日本，东京)及ICGA(海德堡视网膜血管造影II，海德堡工程，德国，海德堡)进行眼底照相及荧光血管造影(fluorescein angiography，FA)。视网膜图像均由两个视网膜专家(P.K.L.和J.H.L.)以隐密的方式进行。只有具有特征性息肉状脉络膜血管扩张(息肉样病变或息肉)的ICGA受试者被诊断为PCV，PCV的位置被分成凹外(extrafoveal)，近中心凹(juxtafoveal，在200微米内凹)、凹下(subfoveal)和乳头周围区域(peripapillary area，在内视盘的盘直径内)。
在本发明的实施例中，所有受试者的数据包括年龄、性别、吸烟、饮酒、服药史的生活方式因素、高血压病史、糖尿病(diabetes mellitus，DM)疾病、冠状动脉疾病、脑血管疾病及肾功能不全等等，但不限于本发明。
总血浆高半胱胺酸分析(total plasma homocysteine analysis)
在本发明的实施例中，以坐姿方式获得空腹静脉血液样本，且收集在含有肝素的试管，接着立即将样本于4℃使用实验室离心机进行离心，以及藉由具有0.5μmol/L的灵敏度及6.8％于4.9μmol/L及3.9％于61.6μmol/L的总变异系数(coeficient of variation，CV)的自动化化学发光免疫(ADVIACentaur system，Siemens，East Walpole，MA，USA)测量血浆高半胱胺酸程度。此外，上述的测定方法亦包括荧光偏振免疫测定法(fluorescent polarizationimmunoassay)及高效液相色谱法(high-performance liquid chromatography，HPLC)。
高敏感度C反应蛋白(high sensitivity C-reactive protein，hsCRP)分析
在本发明的实施例中，本发明获得静脉血液样本，且收集在血清分离管中。藉由比率浊度测定法(rate nephelometry)，利用自动化浊度计(Immage800，Beckman Coulter，Fullerton，CA，USA)测量血清hsCRP。在此hsCRP的测定法中，藉由具有0.2mg/L的分析灵敏度及5.17％于0.79mg/L及3.8％于13.4mg/L的总变异系数，已经显示出本发明的测定方法与其他常用的测定方法具有极佳的相关性。
在本发明的实施例中，高半胱胺酸血症与升高hsCRP的程度分别被定义为高于对照组的九十五百分位的百分位数(95th percentile)程度。
统计分析
在本发明的统计分析方法中，在人口和医疗方面，使用学生t检验(Student’s t-test)及皮尔森卡方检验(Pearsons’s chi-square test)分别对PCV病例和对照组之间的连续和分类变量进行比较。血浆高半胱胺酸及血清hsCRP为中位数(四分位距(interquartile range))，以及由于高半胱胺酸及hsCRP并非为常态分布(normal distribution)，所以藉由Mann-Whitney U检验与对照组相比较。
在本发明的统计分析方法中，多变量逻辑回归模型(multivariable logisticregression model)被用来评估PCV是否与血浆高半胱胺酸或血清hsCRP有关。所有的胜算比(odds ratios，ORs)均依据年龄、性别、生活方式因素(吸烟和饮酒)及疾病史(高血压、糖尿病、冠状动脉疾病及脑血管疾病)进行调整。
另外，在本发明的统计分析方法中，使用SPSS的Windows版本18(SPSS公司，芝加哥，伊利诺伊州，美国)进行本发明的计算。所有的P值均基于双尾检验(two-tailed test)，以及小于0.05的P值被认为是显著性差异(statistical significance)。
结果
在一百二十四名患者中，三名患者被排除由于其肾功能不全，两名患者亦被排除由于其具有AMD的CNV被诊断出。因此，最后共有一百十九名具有PCV患者与对照组相比较。
表1显示息肉状脉络膜血管病变、对照组及P值的比较。
如表1所示，在PCV组及对照组中，平均年龄分别为72.1±13.0年及69.3±10.9年，在这两个群体中，男性占优势(74.8％)。在年龄、性别、高血压、糖尿病、冠状动脉疾病、脑血管疾病及生活方式因素(包括吸烟及饮酒情况下)方面，本发明显示并无显著性差异。
表1：息肉状脉络膜血管病变、对照组及P值的比较
表2显示全体及不同性别的息肉状脉络膜血管病变、对照组及P值的比较。
如表2所示，在中位数血浆高半胱胺酸程度方面，PCV组(中位数，12.20μmol/L，四分位距，9.67-16.66μmol/L)显著地高于对照组(中位数，9.80μmol/L，四分位距，8.13-11.26μmol/L，P＜0.001)。高半胱胺酸的评估可以进一步分为有糖尿病子组及无糖尿病子组。有糖尿病的PCV患者的血浆高半胱胺酸程度显著地高于有糖尿病对照组(p值＝0.001)。此外，无糖尿病的PCV患者的血浆高半胱胺酸程度亦显著地高于无糖尿病对照组(P＜0.001)。在中位数血清hsCRP方面，PCV组(中位数，0.16mg/dl，四分位距，0.06-0.30mg/dl)略高于对照组(中位数，0.11mg/dl，四分位距，0.06-0.25mg/dl，p值＝0.07)。
此外，在对照组中，高半胱胺酸的九十五百分位的百分位数(95thpercentile)为13.26μmol/L。与对照组(P＜0.001)的一百十九名患者中的五名患者(4.2％)相比较，在一百十九名PCV患者中的四十七名患者(39.5％)超过上述临界值。再者，在对照组中的hsCRP的九十五百分位的百分位数为0.70mg/dl。与对照组(p＝0.12)的一百十三名患者中的六名患者(5.4％)相比较，在一百十八名患者中的十三名患者(11.1％)超过上述临界值。
表2：全体及不同性别的息肉状脉络膜血管病变、对照组及P值的比较
表3显示高半胱胺酸及高敏感度C反应蛋白的息肉状脉络膜血管病变、对照组及P值的比较。
如表3所示，在性别方面，与对照组相比较，PCV组的男性及女性具有显著地较高的血浆高半胱胺酸程度(男性，P＜0.001及女姓，P＝0.02)以及高同型半胱胺酸血症的比例(男性，P＜0.001及女性P＝0.02)。hsCRP的结果一般而言为非显著，除了升高的hsCRP在女性部分为较高比例(26.7％对比于对照组中的3.4％，P＝0.01)(如表2所示)。若将高半胱胺酸程度分为三分位数(tertile)，与对照组相比较(67.2％对比于对照组中的32.8％，P＜0.001)，PCV患者的显著较高比例在最高的前三分之一具有高半胱胺酸程度。
表3：高半胱胺酸及高敏感度C反应蛋白的息肉状脉络膜血管病变、对照组及P值的比较
关于多变量逻辑回归分析方面，在调整年龄、性别、高血压、糖尿病，冠状动脉疾病、脑血管疾病、吸烟和饮酒后，本发明指出，升高的血浆高半胱胺酸程度与PCV的增加具有显著性相关(OR，1.54；95％信赖区间(confidence interval，CI)，1.33-1.79，P＜0.001)。具体而言，如表3所示，在回归模型中，患者在高半胱胺酸的最高的前三分之一具有9倍增加风险的PCV(OR，8.8495％CI，3.68-21.21，P＜0.001)。
因此，根据本发明的实施例，本发明的侦测或诊断人类眼部的息肉状脉络膜血管病变的生物标记可包括：确定高同型半胱胺酸血症(Hyperhomocysteinemia)的作用程度，其中，该高同型半胱胺酸血症的作用程度与该人类眼部的息肉状脉络膜血管病变高度相关联。
再者，本发明进一步提供一种侦测或诊断人类眼部的息肉状脉络膜血管病变的方法，本发明的侦测或诊断人类眼部的息肉状脉络膜血管病变的方法包括以下步骤：确定从该人类眼部取得的多个生物样品的高同型半胱胺酸血症的作用程度；以及将该高同型半胱胺酸血症的作用程度与高同型半胱胺酸血症的作用对照程度比较，其中，该高同型半胱胺酸血症的作用程度与该人类眼部的息肉状脉络膜血管病变高度相关联。
根据本发明的实施例，该多个生物样品的数据可包括年龄、性别、生活方式因素、吸烟、饮酒量、用药史、高血压病史、糖尿病病史、冠状动脉疾病病史、脑血管疾病病史，但本发明不限于此。
根据本发明的实施例，该高同型半胱胺酸血症的作用程度可藉由以下分析方法确定：总血浆高半胱胺酸分析(total plasma homocysteine analysis)、高敏感度C反应蛋白分析(high sensitivity C-reactive protein(hsCRP)analysis)及统计分析，但本发明不限于此。
根据本发明的实施例，该统计分析使用多变量逻辑回归模型(multivariable logistic regression model)判断血浆高半胱胺酸及高敏感度C反应蛋白的作用程度与该息肉状脉络膜血管病变的关联性。
根据本发明的实施例，本发明的侦测或诊断人类眼部的息肉状脉络膜血管病变的方法还包括以下步骤：对该人类眼部进行最佳矫正视力检查(best-corrected visual acuity examination)、裂隙灯生物显微镜检查(slit lampbiomicroscopy examination)及眼底镜检查(fundoscopy examination)。
因此，根据本发明的结果，本发明指出，升高的血浆高半胱胺酸及血清hsCRP均与PCV高度地相关联。
然而，上述实施例仅例示性说明本发明的功效，而非用于限制本发明，任何熟悉本领域的技术人员均可在不违背本发明的精神及范畴下，对上述实施例进行修饰与改变。此外，在上述这些实施例中的元件的数量仅为例示性说明，亦非用于限制本发明。因此，本发明的权利保护范围，应如以下的权利要求范围所列。
Claims (9)
1.一种侦测及诊断人类眼部的息肉状脉络膜血管病变的生物标记，其特征在于，包括：
确定高同型半胱胺酸血症的作用程度，其中，该高同型半胱胺酸血症的作用程度与该人类眼部的息肉状脉络膜血管病变高度相关联。
2.如权利要求1所述的侦测及诊断人类眼部的息肉状脉络膜血管病变的生物标记，其特征在于，该高同型半胱胺酸血症的作用程度藉由以下分析方法确定：总血浆高半胱胺酸分析、高敏感度C反应蛋白分析及统计分析。
3.如权利要求2所述的侦测及诊断人类眼部的息肉状脉络膜血管病变的生物标记，其特征在于，该统计分析使用多变量逻辑回归模型判断血浆高半胱胺酸及高敏感度C反应蛋白的作用程度与该息肉状脉络膜血管病变的关联性。
4.如权利要求1所述的侦测及诊断人类眼部的息肉状脉络膜血管病变的生物标记，其特征在于，还包括：对该人类眼部进行最佳矫正视力检查、裂隙灯生物显微镜检查及眼底镜检查。
5.一种侦测及诊断人类眼部的息肉状脉络膜血管病变的方法，其特征在于，包括以下步骤：
确定从该人类眼部取得的多个生物样品的高同型半胱胺酸血症的作用程度；以及
将该高同型半胱胺酸血症的作用程度与高同型半胱胺酸血症的作用对照程度比较，其中，该高同型半胱胺酸血症的作用程度与该人类眼部的息肉状脉络膜血管病变高度相关联。
6.如权利要求5所述的侦测及诊断人类眼部的息肉状脉络膜血管病变的方法，其特征在于，该多个生物样品的数据包括年龄、性别、生活方式因素、吸烟、饮酒量、用药史、高血压病史、糖尿病病史、冠状动脉疾病病史、脑血管疾病病史。
7.如权利要求5所述的侦测及诊断人类眼部的息肉状脉络膜血管病变的方法，其特征在于，该高同型半胱胺酸血症的作用程度藉由以下分析方法确定：总血浆高半胱胺酸分析、高敏感度C反应蛋白分析及统计分析。
8.如权利要求7所述的侦测及诊断人类眼部的息肉状脉络膜血管病变的方法，其特征在于，该统计分析使用多变量逻辑回归模型判断血浆高半胱胺酸及高敏感度C反应蛋白的作用程度与该息肉状脉络膜血管病变的关联性。
9.如权利要求5所述的侦测及诊断人类眼部的息肉状脉络膜血管病变的方法，其特征在于，还包括：对该人类眼部进行最佳矫正视力检查、裂隙灯生物显微镜检查及眼底镜检查。
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