CN113287019A - 亚临床动脉粥样硬化的生物标志物 - Google Patents
亚临床动脉粥样硬化的生物标志物 Download PDFInfo
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Abstract
本发明涉及PIGR、APOA、HPT、HEP2、C5、ITIH1和IGHA2作为亚临床动脉粥样硬化的筛选、诊断和/或监测的生物标志物,以及使用它们的方法和试剂盒。
Description
发明领域
本发明涉及诊断学领域。特别地,本发明涉及用于亚临床动脉粥样硬化的筛选、诊断和/或监测的蛋白质生物标志物及其使用方法和试剂盒。
发明背景
与动脉粥样硬化疾病的临床管理相关的挑战之一是它通常被诊断得太迟,通常当病情非常严重并且病变已经不可逆转时,或者当它已经在由患病动脉供血的器官或区域中引起临床征象或事件时。
初级预防目前是基于根据标准化建议评估可改变的风险因素。然而,已经发现,在每个风险因素暴露水平下,动脉粥样硬化的量都存在显著的变化(Fernandez-Ortiz A等人,Am Heart J 2013;166:990-8)。
通过成像方法对中年人的亚临床动脉粥样硬化负荷的非侵入性测量具有改善心血管风险评估的潜力,并且可以有助于更有效地预防心血管事件。然而,最近的指南(PerkJ等人,Eur Heart J 2012;33:1635-701)仅推荐在被视为处于中等风险的无症状成年人中进行这些成像测试(Fernandez-Ortiz A等人,2013)。
亚临床动脉粥样硬化进展和早期检测(PESA)的研究是旨在表征亚临床动脉粥样硬化的患病率和与中年无症状群体中疾病的存在和进展相关的决定因素的纵向队列研究。
有趣的是,在PESA研究中显示了相当大比例的基于传统心血管风险评分(即,FHS-10年)被分类为低风险的无症状个体具有广泛的动脉粥样硬化(Fernandez-Friera L等人,Circulation.2015;131:2104-2113)。
作者进行了旨在鉴定在单一区域(病灶疾病)中亚临床动脉粥样硬化的参与者与具有多个区域(中间或全身性疾病)的参与者之间的差异分析。该分析的结果证明了动脉粥样硬化的程度与心血管风险(CVR)评分和大多数CVR因子之间的统计学上显著的关联。Fernandez-Friera L等人,2015还公开了通过传统风险因素评分量表分类为高风险的大多数个体患有亚临床动脉粥样硬化,其中高比例患有中间或全身性疾病。
然而,亚临床动脉粥样硬化也存在于被分类为低风险的60%的个体中,表明动脉粥样硬化与标准风险量表中未考虑的特征的关联。这是一种惊人的观察结果,因为呈现多区域亚临床动脉粥样硬化的个体,尽管被分类为低风险,但将更可能发展动脉粥样硬化性心血管疾病(ASCVD)事件。
Fernandez-Friera L等人,2017(J Am Coll Cardiol.2017;70(24):2979-2991)也涉及PESA研究并报道了许多没有CVR因子的中年个体出现动脉粥样硬化。该研究已经发现LDL-胆固醇(LDL-C)水平,甚至在当前认为正常的水平下,也与亚临床动脉粥样硬化的存在和程度独立相关。因此,指出即使在被认为处于低风险的个体中也采用LDL-C的降低作为预防措施。
在亚临床环境中鉴定动脉粥样硬化的生物标志物在技术上比在良好发展的CVD或急性CV事件的情况下更具挑战性,其中预期疾病对血浆蛋白水平具有明显的影响。极少数的研究已经评估了亚临床动脉粥样硬化的潜在血浆蛋白生物标志物。免疫测定已经用于定量特定血浆蛋白脂连蛋白(Saarikoski LA等人,2010)和TIMP4(Oikonen M等人,2012)的改变,显示了在年轻芬兰人队列的心血管风险中,这些蛋白在患有无症状的亚临床颈动脉粥样硬化的个体中降低。对年轻芬兰人队列中心血管风险的发现蛋白质组学分析发现在中年个体中FBLN1C血浆水平与斑块存在之间的关联(Bhosale SD等人,2018),并且通过同一群体中的靶向蛋白质组学来确认结果。然而,在我们的研究中,FBLN1C没有通过所使用的严格的过滤标准。
Yin X等人,2014(Arteriosclerosis,thrombosis,and vascular biology 2014,34:939-945)涉及鉴定新的血浆蛋白生物标志物,其单独地或总体预测ASCVD的风险。该文献显示了在单一标志物分析中PIGR与心肌梗塞之间的关联。
Ngo D等人,2016(Circulation 2016,134:270-285)旨在弗雷明汉心脏研究(Framingham Heart Study,FHS)中检测血浆蛋白浓度与弗雷明汉风险评分组成之间的关联。特别地,它提及血浆中PIGR水平与吸烟之间的关联。吸烟是得到确认的心脏风险因素,并且是FHS风险评估算法中的变量之一。还报道了PIGR与冠心病FHS评分相关。
因此,需要找到新的生物标志物,用于对呈现亚临床动脉粥样硬化的个体进行筛选、诊断和/或监测。此外,特别需要鉴定独立于传统CVR因子和评分的标志物,以便能够从被分类为具有低心血管风险的对象中检测出那些呈现出亚临床动脉粥样硬化的对象。
发明内容
据我们所知,本申请提供了迄今为止在寻找动脉粥样硬化相关的生物标志物中最深入和最大的基于质谱的血浆蛋白质组学分析的结果。本申请的发明人使用了能够在来自PESA研究的444名个体的队列中定量来自未耗损血浆样品的超过1000种蛋白质的蛋白质组学平台。通过将由多重同重元素标记提供的定量准确度和稳健性与良好验证和自动统计工作流相结合,这种分析是可能的(Navarro P和Vazquez J,2014;Garcia-Marques F等人,2016;Trevisan-Herraz M等人,2018)。在3年的随访中对从同一个体获得的血浆样品进行的第二次分析验证了结果并鉴定了一组推定的生物标志物蛋白,其与动脉粥样硬化的关联随时间保持稳定。在第二次访问中的这种验证对于减少发现阶段中的误差源,丢弃具有显著生物变异性的蛋白质以及集中精力于可用于检测亚临床动脉粥样硬化的稳健的生物标志物组是必不可少的。
本申请的发明人已经发现通过液相色谱串联质谱(LC-MS/MS)分析测定的血浆中PIGR(聚合免疫球蛋白受体)、APOA(载脂蛋白(a))、HPT(触珠蛋白)、HEP2(肝素辅因子2)、C5(补体组分5)、ITIH1(间α胰蛋白酶抑制剂1)和IGHA2(免疫球蛋白重链恒定区α2(immunoglobulin heavy constant alpha 2))的水平彼此独立地与亚临床动脉粥样硬化疾病相关以及与确立的心血管风险因素(例如,年龄、吸烟)和心血管风险等级(例如,FHS风险评分)相关。
此外,随着斑块从脂肪条纹型发展为纤维脂质病变型,这些蛋白质在中间层中以及主要在内膜层(斑块)中的累积已经显示更高(参见图1和图5)。因此,本申请的发明人也将这些蛋白质的水平与动脉粥样硬化的进展程度相关联。
在此基础上,本申请的发明人提出了这些生物标志物,优选其组合,用于本文所述的亚临床动脉粥样硬化的筛选、诊断和/或监测的方法中。
因此,本发明的第一方面涉及用于筛选、诊断和/或监测对象中的亚临床动脉粥样硬化的方法,其包括测定从对象分离的生物样品中的选自PIGR、APOA、HPT、HEP2、C5、ITIH1和IGHA2的一种或多种蛋白标志物的水平,其中所述方法包括:
a)测定从所述对象分离的生物样品中的一种或多种所述生物标志物的蛋白质表达水平;以及
b)将所述生物标志物的水平与参考值进行比较;
c)其中当所述对象的样品中PIGR、IGHA2、APOA、HPT、HEP2、ITIH1和/或C5的水平相对于相应的参考值增加时,表明亚临床动脉粥样硬化。
在第二方面,本发明提供了用于治疗患有亚临床动脉粥样硬化的对象的方法,其中所述方法包括:
a.通过如本文所定义的用于筛选、诊断和/或监测的方法鉴定患有亚临床动脉粥样硬化的对象;
b.向所述患者施用治疗有效量的用于预防/减少动脉粥样硬化斑块的合适治疗。
在另一方面,本发明涉及用于测定从对象分离的生物样品中如本文所述的一种或多种蛋白质标志物的水平的试剂盒。所述试剂盒还可以含有指示可以如何使用所述试剂盒内的材料的说明书。
在另外的方面,本发明涉及前述方面的试剂盒在用于如本文所述的亚临床动脉粥样硬化的筛选、诊断和/或监测的方法中的用途。
附图简述
图1:在来自人类主动脉的样品的中间层和内膜层中PIGR(图1A)、APOA(图1B)、ITIH1(图1C)、C5(图1D)和IGHA2(图1E)水平的定量蛋白质组学分析(对照;具有脂肪条纹(FS)的动脉粥样硬化斑块和具有纤维脂质病变(FL)的斑块)。用星号(*)突出显示了统计显著结果,其中*意指p值为0.05,**意指p值为0.01,***意指p值为0.001,并且****意指p值为0.0001,并且参考值是健康组。
图2:血浆蛋白水平与传统CV风险因素的关联
通过分析每一个连续的风险因素与通过蛋白质组学定量的每一种蛋白质的血浆水平的相关性来构建网络。在PESA-V1和PESA-V2中通过邦费罗尼(Bonferroni)校正的p值<0.05来选择统计学上显著的相关性,并且皮尔森相关系数(Pearson's correlationcoefficients)被用作权重以使用Cytoscape构建相关性网络。线条的粗细与权重成正比(深灰色:正相关;浅灰色:负相关)。还显示了风险因素之间的相关性。DBP:舒张压;SBP:收缩压;LDL:低密度脂蛋白;Ch:胆固醇;HDL:高密度脂蛋白;APOB:载脂蛋白B-100;PRG4:蛋白聚糖4;PCYOX1:异戊烯半胱氨酸氧化酶1;P06309:免疫球蛋白κ可变2D-28(GeneNameIGKV2D-28);APOM:载脂蛋白M;APOE:载脂蛋白E;APOC3:载脂蛋白C-III;APOC2:载脂蛋白C-II;THRB:凝血酶原;PLTP:磷脂转移蛋白;APOF:载脂蛋白F;PON3:血清对氧磷酶/内酯酶3;CFB:补体因子B;APOA1:载脂蛋白A-I;ApoA2:载脂蛋白A-II。
图3:PESA-V1和PESA-V2队列中血浆蛋白与斑块厚度和CACS的相关性。
(A)将在PESA-V1中获得的相对血浆蛋白水平与斑块厚度(皮尔森相关系数)的相关性与在PESA-V2中获得的那些进行比较。点大小表示血浆中的蛋白质丰度(以每种蛋白质定量的肽的数量表示)。插图显示了与体液免疫应答相关的蛋白质的行为,以及产生显著相关性的其它蛋白质的行为。
(B)PESA-V1和PESA-V2中的相对血浆水平与CACS的相关性。数据如(A)中所示。
图4:显示了所选蛋白质在PESA-V1中亚临床动脉粥样硬化(病例对比对照)的比值比的森林图。
比值比是指通过蛋白质组学测定的并且使用单变量逻辑回归模型(未调整的)或通过常见风险评分(FHS 10年,BEWAT或ICHS)调整的多变量模型以标准偏差为单位表示的相对蛋白质值。误差柱条表示95%的置信区间。
图5:人类动脉粥样硬化组织样品中五种所选蛋白质的绝对蛋白质丰度水平。
通过蛋白质组学对五种蛋白质进行绝对定量,并且它们的水平相对于每个样品的总蛋白质量进行表达。在来自中间层(从健康主动脉获得,或从显示早期斑块(具有纤维脂质病变或具有脂肪条纹)的主动脉获得),或来自内膜层(具有纤维脂质病变或具有脂肪条纹)的样品中测量水平。使用学生t-检验计算蛋白质丰度变化相对于健康样品的蛋白质丰度变化的指示的统计显著性。
图6显示了所选蛋白质在AWHS中亚临床动脉粥样硬化(病例对比对照)的比值比的森林图。
比值比是指如通过比浊法测定的并且使用单变量逻辑回归模型(未调整的)或通过常见风险评分(FHS 10年,BEWAT或ICHS)调整的多变量模型以标准偏差为单位表示的蛋白质值。误差柱条表示95%的置信区间。
图7:显示了在针对PESA-V1和AWHS中亚临床动脉粥样硬化的改善的预测的蛋白质生物标志物组(panel)的ROC分析之后的曲线下面积的森林图。误差柱条表示AUC值的95%置信区间。星号表示AUC显著优于单独使用风险评分获得的AUC的统计显著性。
图8:显示了在针对PESA-V1和AWHS中具有低风险(FHS 10年<0.1)个体的亚临床动脉粥样硬化的改善的预测的蛋白质生物标志物组(panel)的ROC分析之后的曲线下面积的森林图。误差柱条表示AUC值的95%置信区间。星号表示AUC显著优于0.5的统计显著性。
发明详述
定义
术语“对象”或“个体”在本文中可互换地用于指被分类为哺乳动物的所有动物,并且包括但不限于家畜和农场动物、灵长类动物和人类,例如人、非人类灵长类动物、牛、马、猪、绵羊、山羊、狗、猫或啮齿动物。优选地,对象是任何年龄或种族的男性或女性。
本文所用的术语“诊断”是指试图确定和/或鉴定对象中可能疾病的过程,即诊断程序,以及通过该过程所达成的意见,即诊断意见。
术语“筛选”在本文中被理解为检查或测试属于一般人群的一组无症状个体,或者具有一个或多个风险因素的一组个体(即,疑似发展疾病或处于发展疾病的风险中的对象),目的是将健康个体与患有或疑似患有疾病的那些个体区分开来。筛选的方法通常用于疾病的“早期检测”。表述“早期检测”是指在存在临床征象之前进行检测。
本文所用的术语“监测”是指确定疾病的演变和/或疗法的功效,例如确定是否存在疾病的缓解;或者相反,是否存在疾病进展或复发。
本文所用的术语“生物标志物”是指疾病的标志物,其通常是在身体样品中发现的可以容易地被测量的物质。测量的量可以与潜在的疾病病理生理学,如是否存在亚临床动脉粥样硬化,或者与其预后(即,克服潜在疾病的可能性)相关。在接受对其病况治疗的患者中,测量的量也可能与对治疗的响应相关。
本文所用的术语“治疗有效量”是指在疾病、病症或病理学病况的预防性或治疗性治疗中向对象(如人类患者)单剂量或多剂量施用时有效的量。
本文所用的术语“基本上相同的”序列是指与参考序列至少约95%,优选至少约96%、97%、98%或99%相同的序列。两个序列之间的同一性百分比可以通过本领域已知的任何手段,例如Needleman和Wunsch全局比对算法确定。
术语“亲和试剂”可以指配体(例如,抗体、肽、蛋白质、核酸或小分子),其通过特异性分子识别(通常具有纳摩尔至亚纳摩尔范围的结合亲和力)选择性地捕获(结合)靶分子。例如,亲和试剂可以是适配体、抗体或抗体模拟物。
本文所用的术语“亲和力”可以指抗原与抗原结合分子解离的平衡常数(KD),并且被认为是抗原决定簇与抗原结合分子上的抗原结合位点之间的结合强度的量度:KD值越小,抗原决定簇与抗原结合分子之间的结合强度越强(可选地,亲和力也可以表示为缔合常数(KA),其是1/KD)。本领域技术人员将清楚,解离常数可以是实际的或表观的解离常数。
本文所用的术语“适配体”或“核酸适配体”可以指分离的或纯化的单链核酸(RNA或DNA),其通过沃森-克里克碱基配对以外的相互作用以高的特异性和亲和力与靶标结合。适配体具有提供与靶标特异性结合的化学接触的三维结构。与传统的核酸结合不同,适配体结合不依赖于保守的线性碱基序列,而是依赖于特定的二级或三级结构。也就是说,适配体的核酸序列是非编码序列。适配体可能具有的任何编码潜能是完全偶然的,并且在适配体与靶标的结合中不起任何作用。典型的最小化适配体大小为5-15kDa(15-45个核苷酸),以纳摩尔至亚纳摩尔的亲和力与靶标结合,并与密切相关的靶标相区别(例如,适配体通常不与来自相同基因或功能家族的其它蛋白结合)。
本文所用的术语“抗体”可以指免疫球蛋白或其抗原结合片段。除非另有说明,否则该术语包括但不限于多克隆的、单克隆的、单特异性的、多特异性的、人源化的、人类的、嵌合的、合成的、重组的、杂合的、突变的、移植的和体外产生的抗体。抗体可以包括恒定区或其部分,如κ、λ、α、γ、δ、ε和μ恒定区基因。例如,可以使用各种同种型的重链恒定区,包括:IgG1、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgD和IgE。例如,轻链恒定区可以是κ或λ。在某些实施方案中,术语“抗体”还可以指抗体衍生物,如基于抗体的融合蛋白(例如,包括与免疫球蛋白的Fc区等同的区域)或进一步修饰以含有另外的非蛋白质部分,如水溶性聚合物,例如聚乙二醇(PEG)的抗体。
术语“抗原结合域”和“抗原结合片段”是指抗体分子的一部分,其包含负责抗体和抗原之间特异性结合的氨基酸。对于某些抗原,抗原结合结构域或抗原结合片段可以仅结合抗原的一部分。被抗体特异性识别和结合的抗原部分被称为“表位”或“抗原决定簇”。抗原结合结构域和抗原结合片段包括Fab;F(ab')2片段(具有在铰链区通过二硫键连接的两个Fab片段的二价片段);Fv片段;单链Fv片段(scFv);Fd片段(具有两个VH和CH1结构域);单域抗体(sdAb;由单一VH结构域组成)和保留抗原结合功能的其它抗体片段。Fab片段具有通过恒定区之间的二硫键共价连接的VH-CH1和VL-CL结构域。Fv片段较小并且具有非共价连接的VH和VL结构域。scFv含有连接(1)VH的C-末端与VL的N-末端,或者(2)VL的C-末端与VH的N-末端的柔性多肽。sdAb包括天然缺乏轻链的重链抗体和衍生自常规的四链抗体的单域抗体。使用本领域技术人员已知的常规技术获得这些抗原结合结构域和片段,并以与完整免疫球蛋白相同的方式评价其功能。
本文所用的术语“重组抗体”是指使用重组表达载体产生或表达的抗体,其中表达载体包含编码重组抗体的核酸,使得将表达载体引入适当的宿主细胞导致重组抗体的产生或表达。重组抗体可以是嵌合抗体或人源化抗体、单特异性抗体或多特异性抗体。
本文所用的术语“抗体模拟物”可以指基于蛋白质的支架,其已经被工程化以与天然抗体匹配的亲和力和特异性结合治疗靶标。已经利用免疫球蛋白样折叠,例如III型纤连蛋白、NCAM和CTLA-4开发了抗体模拟物。还获得了与免疫球蛋白折叠没有相似性的其它模拟支架。所述支架的非限制性实例是DARPins、anticalins、affibodies、adnectins、fynomers等(参见,例如Weidle等人,2013,Cancer Genomics&Proteomics,10,1-18;Lofblom,J.等人,2011,Curr.Opin.Biotechnol.,22,843–848;Banta,S.等人,2010,Annu.Rev.Biomed.Eng.,15,93–113)。
本发明的方法
在第一方面,本发明提供了用于筛选、诊断和/或监测对象中的亚临床动脉粥样硬化的方法,所述方法包括测定从对象分离的生物样品中的选自PIGR、APOA、HPT(触珠蛋白)、HEP2(肝素辅因子2)、C5、ITIH1和IGHA2的一种或多种蛋白标志物的水平,其中所述方法包括:
a)测定从所述对象分离的生物样品中的一种或多种所述生物标志物的蛋白质表达水平;以及
b)将所述生物标志物的水平与参考值进行比较;
c)其中当所述对象的样品中PIGR、IGHA2、APOA、HPT、HEP2、ITIH1和/或C5的水平相对于相应的参考值增加时,表明亚临床动脉粥样硬化。
此外,本申请的发明人已经将PIGR、IGHA2、APOA、HPT、HEP2、ITIH1和C5在斑块中的累积与动脉粥样硬化的进展程度相关联(参见图1和图5)。因此,在本发明的筛选、诊断和/或监测方法中测定这些蛋白质的血浆水平也可以提供关于或能够预测亚临床动脉粥样硬化进展程度的信息。
本文所用的术语“亚临床动脉粥样硬化”是指无症状个体中的动脉粥样硬化。表述“无症状个体”是指先前没有经历心血管疾病(包括例如心肌梗塞、心绞痛或中风)的临床征象的那些对象。
优选地,“亚临床动脉粥样硬化”是指在无症状个体的颈动脉、主动脉或髂股区中存在动脉粥样硬化斑块或者CACS≥1。根据受累的血管部位(右颈动脉、左颈动脉、腹主动脉、右髂股、左髂股和冠状动脉)的数目来定义亚临床动脉粥样硬化的多区域“范围”。例如,如实施例中详细说明的,在PESA研究中,根据成像测定的结果(“PESA评分”)将参与者分类为四个不同类别,即无疾病(受累的0个血管部位)或具有病灶(1个部位)、中间(2-3个部位)或全身性(4-6个部位)动脉粥样硬化。
可以通过颈动脉、肾下腹主动脉和髂股动脉的横断面扫描来评估“动脉粥样硬化斑块的存在”。术语“斑块”通常是指进入动脉管腔的厚度>0.5mm或>50%的周围内膜-中层厚度或在中层-外膜和内膜-管腔界面之间测量的扩散厚度>1.5mm的局部突出物。
本发明的第一方面的方法中的步骤(a)包括测定所述生物样品中一种或多种如上定义的蛋白质标志物的表达水平。
PIGR(聚合免疫球蛋白受体)在上皮细胞的基底外侧表面结合聚合的IgA和IgM分子;然后将复合物转运穿过待在顶端表面分泌的细胞。在此过程中,发生裂解,其将细胞外(称为分泌组分)与跨膜区段分开。人类PIGR的规范序列被称为SEQ ID NO:1(UniProtKB登录号P01833-1;这是2007年6月26日第4版的序列):
MLLFVLTCLLAVFPAISTKSPIFGPEEVNSVEGNSVSITCYYPPTSVNRHTRKYWCRQGARGGCITLISSEGYVSSKYAGRANLTNFPENGTFVVNIAQLSQDDSGRYKCGLGINSRGLSFDVSLEVSQGPGLLNDTKVYTVDLGRTVTINCPFKTENAQKRKSLYKQIGLYPVLVIDSSGYVNPNYTGRIRLDIQGTGQLLFSVVINQLRLSDAGQYLCQAGDDSNSNKKNADLQVLKPEPELVYEDLRGSVTFHCALGPEVANVAKFLCRQSSGENCDVVVNTLGKRAPAFEGRILLNPQDKDGSFSVVITGLRKEDAGRYLCGAHSDGQLQEGSPIQAWQLFVNEESTIPRSPTVVKGVAGGSVAVLCPYNRKESKSIKYWCLWEGAQNGRCPLLVDSEGWVKAQYEGRLSLLEEPGNGTFTVILNQLTSRDAGFYWCLTNGDTLWRTTVEIKIIEGEPNLKVPGNVTAVLGETLKVPCHFPCKFSSYEKYWCKWNNTGCQALPSQDEGPSKAFVNCDENSRLVSLTLNLVTRADEGWYWCGVKQGHFYGETAAVYVAVEERKAAGSRDVSLAKADAAPDEKVLDSGFREIENKAIQDPRLFAEEKAVADTRDQADGSRASVDSGSSEEQGGSSRALVSTLVPLGLVLAVGAVAVGVARARHRKNVDRVSIRSYRTDISMSDFENSREFGANDNMGASSITQETSLGGKEEFVATTESTTETKEPKKAKRSSKEEAEMAYKDFLLQSSTVAAEAQDGPQEA。
本文所用的术语“PIGR”是指具有SEQ ID NO:1的人类PIGR蛋白以及与其基本相同序列。优选地,所述序列是SEQ ID NO:1。
人类免疫球蛋白重链恒定α2(IGHA2)的规范序列被称为SEQ ID NO:2(UniProtKB登录号P01877-1;这是2017年3月15日第4版的序列):
ASPTSPKVFPLSLDSTPQDGNVVVACLVQGFFPQEPLSVTWSESGQNVTARNFPPSQDASGDLYTTSSQLTLPATQCPDGKSVTCHVKHYTNSSQDVTVPCRVPPPPPCCHPRLSLHRPALEDLLLGSEANLTCTLTGLRDASGATFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAQPWNHGETFTCTAAHPELKTPLTANITKSGNTFRPEVHLLPPPSEELALNELVTLTCLARGFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTYAVTSILRVAAEDWKKGETFSCMVGHEALPLAFTQKTIDRMAGKPTHINVSVVMAEADGTCY。
本文所用的术语“IGHA2”是指具有SEQ ID NO:2的人类IGHA2蛋白以及与其基本相同序列。优选地,所述序列是SEQ ID NO:2。
PIGR和IGHA2在早期动脉粥样硬化病变中的存在是一个新发现。PIGR和IGHA2在功能上是相关的,并且已知参与体液免疫应答。IgA免疫球蛋白被认为是粘膜表面处抗原特异性免疫保护的第一线,而PIGR是结合肠上皮细胞的基底外侧表面处循环的聚合IgA和IgM并且将它们转运穿过待在顶端表面分泌的细胞进入肠腔中的受体(Kaetzel CS,2005;WinesBD和Hogarth PM,2006)。尽管目前认为动脉粥样硬化是一种具有强自身免疫成分和来自先天和适应性免疫的明显贡献的慢性免疫炎症疾病(Hansson GK和Hermansson A,2011),但关于IgA抗体在CV疾病中的作用的信息很少(Tsiantoulas D等人,2014)。已经报道PIGR水平在吸烟者和慢性阻塞性肺病患者的痰和血液中增加(Ohlmeier S等人,2012);此外,PIGR与来自弗雷明汉(Framingham)后代研究的队列中的吸烟有关,尽管PIGR水平与该队列中的CV疾病无关(Ngo D等人,2016)。我们意识到的PIGR与动脉粥样硬化之间的唯一联系是来自患有急性冠状动脉综合征的个体的细胞外囊泡中该蛋白的水平升高,尽管与常规风险因素或肌钙蛋白I相比,该参数的包含并没有改善疾病检测(de Hoog VC等人,2013)。以前没有报道过IgA同种型IGHA2与动脉粥样硬化之间的关联;然而,已经报道了与晚期动脉粥样硬化或末期CV事件相关的升高的总血清IgA(其包括IGHA1(最丰富的同种型)和IGHA2);例如,在患有严重动脉粥样硬化(Muscari A等人,1988)或者具有先前的心肌梗塞或其它严重缺血性事件(Muscari A等人,1993)的患者。IgA的水平以及IgE和IgG的水平(而非IgM的水平)也与血脂异常男性的心肌梗塞和心脏死亡相关(Kovanen PT等人,1998)。
载脂蛋白(a)(APOA)是脂蛋白(a)(LPA)的主要成分。已知APOA被蛋白水解裂解,并且片段在动脉粥样硬化病变中累积。APOA是众所周知的累积在内膜中;该蛋白含有赖氨酸结合位点,其允许其紧密结合裸露内皮(denuded endothelium)上的暴露表面,进入并累积到内膜下空间(Tsimikas S,2017)。有大量证据将APOA与动脉粥样硬化联系起来。尽管Lp(a)在人类中的生理作用仍未完全阐明(Orso E和Schmitz G,2017),但该颗粒已经被鉴定为冠状动脉钙化的独立预测因子(Greif M等人,2013),并且流行病学支持升高的Lp(a)与动脉粥样硬化CV疾病结果之间的强关联(Ellis KL等人,2017),表明Lp(a)在疾病中起因果作用(Ellis KL和Watts GF,2018)。没有特别降低Lp(a)的治疗,因此尚未证明降低Lp(a)对CVD风险的潜在影响;然而,一些当局建议在某些临床情况下测试Lp(a)水平,例如在具有过早CAD的个人史或家族史或者处于中度/高CAD风险的个体中(Ellis KL和Watts GF,2018)。
我们的结果首次证明了APOA蛋白水平作为亚临床阶段中动脉粥样硬化的独立预测因子的潜力,补充了不仅由已知的风险因素而且由IGAH2和HPT提供的信息。
人类APOA的规范序列被称为SEQ ID NO:3(UniProtKB登录号P08519;这是1988年8月1日第1版的序列):
MEHKEVVLLLLLFLKSAAPEQSHVVQDCYHGDGQSYRGTYSTTVTGRTCQAWSSMTPHQHNRTTENYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPGVRWEYCNLTQCSDAEGTAVAPPTVTPVPSLEAPSEQAPTEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHSRTPEYYPNAGLIMNYCRNPDPVAAPYCYTRDPSVRWEYCNLTQCSDAEGTAVAPPTITPIPSLEAPSEQAPTEQRPGVQECYHGNGQSYQGTYFITVTGRTCQAWSSMTPHSHSRTPAYYPNAGLIKNYCRNPDPVAAPWCYTTDPSVRWEYCNLTRCSDAEWTAFVPPNVILAPSLEAFFEQALTEETPGVQDCYYHYGQSYRGTYSTTVTGRTCQAWSSMTPHQHSRTPENYPNAGLTRNYCRNPDAEIRPWCYTMDPSVRWEYCNLTQCLVTESSVLATLTVVPDPSTEASSEEAPTEQSPGVQDCYHGDGQSYRGSFSTTVTGRTCQSWSSMTPHWHQRTTEYYPNGGLTRNYCRNPDAEISPWCYTMDPNVRWEYCNLTQCPVTESSVLATSTAVSEQAPTEQSPTVQDCYHGDGQSYRGSFSTTVTGRTCQSWSSMTPHWHQRTTEYYPNGGLTRNYCRNPDAEIRPWCYTMDPSVRWEYCNLTQCPVMESTLLTTPTVVPVPSTELPSEEAPTENSTGVQDCYRGDGQSYRGTLSTTITGRTCQSWSSMTPHWHRRIPLYYPNAGLTRNYCRNPDAEIRPWCYTMDPSVRWEYCNLTRCPVTESSVLTTPTVAPVPSTEAPSEQAPPEKSPVVQDCYHGDGRSYRGISSTTVTGRTCQSWSSMIPHWHQRTPENYPNAGLTENYCRNPDSGKQPWCYTTDPCVRWEYCNLTQCSETESGVLETPTVVPVPSMEAHSEAAPTEQTPVVRQCYHGNGQSYRGTFSTTVTGRTCQSWSSMTPHRHQRTPENYPNDGLTMNYCRNPDADTGPWCFTMDPSIRWEYCNLTRCSDTEGTVVAPPTVIQVPSLGPPSEQDCMFGNGKGYRGKKATTVTGTPCQEWAAQEPHRHSTFIPGTNKWAGLEKNYCRNPDGDINGPWCYTMNPRKLFDYCDIPLCASSSFDCGKPQVEPKKCPGSIVGGCVAHPHSWPWQVSLRTRFGKHFCGGTLISPEWVLTAAHCLKKSSRPSSYKVILGAHQEVNLESHVQEIEVSRLFLEPTQADIALLKLSRPAVITDKVMPACLPSPDYMVTARTECYITGWGETQGTFGTGLLKEAQLLVIENEVCNHYKYICAEHLARGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYARVSRFVTWIEGMMRNN。
本文所用的术语“APOA”是指具有SEQ ID NO:3的人类APOA蛋白以及与其基本相同的序列。优选地,所述序列是SEQ ID NO:3。
间-α-胰蛋白酶抑制剂重链H1(ITIH1)可以充当血清中透明质酸的载体或充当透明质酸与其它基质蛋白(包括组织中细胞表面上的那些)之间的结合蛋白以调节透明质酸的定位、合成和降解,这对于经历生物过程的细胞是必不可少的。人类ITIH1的规范序列被称为SEQ ID NO:4(UniProtKB登录号P19827;这是1998年7月15日第3版的序列):
MDGAMGPRGLLLCMYLVSLLILQAMPALGSATGRSKSSEKRQAVDTAVDGVFIRSLKVNCKVTSRFAHYVVTSQVVNTANEAREVAFDLEIPKTAFISDFAVTADGNAFIGDIKDKVTAWKQYRKAAISGENAGLVRASGRTMEQFTIHLTVNPQSKVTFQLTYEEVLKRNHMQYEIVIKVKPKQLVHHFEIDVDIFEPQGISKLDAQASFLPKELAAQTIKKSFSGKKGHVLFRPTVSQQQSCPTCSTSLLNGHFKVTYDVSRDKICDLLVANNHFAHFFAPQNLTNMNKNVVFVIDISGSMRGQKVKQTKEALLKILGDMQPGDYFDLVLFGTRVQSWKGSLVQASEANLQAAQDFVRGFSLDEATNLNGGLLRGIEILNQVQESLPELSNHASILIMLTDGDPTEGVTDRSQILKNVRNAIRGRFPLYNLGFGHNVDFNFLEVMSMENNGRAQRIYEDHDATQQLQGFYSQVAKPLLVDVDLQYPQDAVLALTQNHHKQYYEGSEIVVAGRIADNKQSSFKADVQAHGEGQEFSITCLVDEEEMKKLLRERGHMLENHVERLWAYLTIQELLAKRMKVDREERANLSSQALQMSLDYGFVTPLTSMSIRGMADQDGLKPTIDKPSEDSPPLEMLGPRRTFVLSALQPSPTHSSSNTQRLPDRVTGVDTDPHFIIHVPQKEDTLCFNINEEPGVILSLVQDPNTGFSVNGQLIGNKARSPGQHDGTYFGRLGIANPATDFQLEVTPQNITLNPGFGGPVFSWRDQAVLRQDGVVVTINKKRNLVVSVDDGGTFEVVLHRVWKGSSVHQDFLGFYVLDSHRMSARTHGLLGQFFHPIGFEVSDIHPGSDPTKPDATMVVRNRRLTVTRGLQKDYSKDPWHGAEVSCWFIHNNGAGLIDGAYTDYIVPDIF。
本文所用的术语“ITIH1”是指具有SEQ ID NO:4的人类ITIH1蛋白以及与其基本相同的序列。优选地,所述序列是SEQ ID NO:4。
人类补体C5被C5转化酶活化会启动晚期补体成分C5-C9自发组装成膜攻击复合物。人类C5的规范序列被称为SEQ ID NO:5(UniProtKB登录号P01031-1;这是2008年2月5日第4版的序列):
MGLLGILCFLIFLGKTWGQEQTYVISAPKIFRVGASENIVIQVYGYTEAFDATISIKSYPDKKFSYSSGHVHLSSENKFQNSAILTIQPKQLPGGQNPVSYVYLEVVSKHFSKSKRMPITYDNGFLFIHTDKPVYTPDQSVKVRVYSLNDDLKPAKRETVLTFIDPEGSEVDMVEEIDHIGIISFPDFKIPSNPRYGMWTIKAKYKEDFSTTGTAYFEVKEYVLPHFSVSIEPEYNFIGYKNFKNFEITIKARYFYNKVVTEADVYITFGIREDLKDDQKEMMQTAMQNTMLINGIAQVTFDSETAVKELSYYSLEDLNNKYLYIAVTVIESTGGFSEEAEIPGIKYVLSPYKLNLVATPLFLKPGIPYPIKVQVKDSLDQLVGGVPVTLNAQTIDVNQETSDLDPSKSVTRVDDGVASFVLNLPSGVTVLEFNVKTDAPDLPEENQAREGYRAIAYSSLSQSYLYIDWTDNHKALLVGEHLNIIVTPKSPYIDKITHYNYLILSKGKIIHFGTREKFSDASYQSINIPVTQNMVPSSRLLVYYIVTGEQTAELVSDSVWLNIEEKCGNQLQVHLSPDADAYSPGQTVSLNMATGMDSWVALAAVDSAVYGVQRGAKKPLERVFQFLEKSDLGCGAGGGLNNANVFHLAGLTFLTNANADDSQENDEPCKEILRPRRTLQKKIEEIAAKYKHSVVKKCCYDGACVNNDETCEQRAARISLGPRCIKAFTECCVVASQLRANISHKDMQLGRLHMKTLLPVSKPEIRSYFPESWLWEVHLVPRRKQLQFALPDSLTTWEIQGVGISNTGICVADTVKAKVFKDVFLEMNIPYSVVRGEQIQLKGTVYNYRTSGMQFCVKMSAVEGICTSESPVIDHQGTKSSKCVRQKVEGSSSHLVTFTVLPLEIGLHNINFSLETWFGKEILVKTLRVVPEGVKRESYSGVTLDPRGIYGTISRRKEFPYRIPLDLVPKTEIKRILSVKGLLVGEILSAVLSQEGINILTHLPKGSAEAELMSVVPVFYVFHYLETGNHWNIFHSDPLIEKQKLKKKLKEGMLSIMSYRNADYSYSVWKGGSASTWLTAFALRVLGQVNKYVEQNQNSICNSLLWLVENYQLDNGSFKENSQYQPIKLQGTLPVEARENSLYLTAFTVIGIRKAFDICPLVKIDTALIKADNFLLENTLPAQSTFTLAISAYALSLGDKTHPQFRSIVSALKREALVKGNPPIYRFWKDNLQHKDSSVPNTGTARMVETTAYALLTSLNLKDINYVNPVIKWLSEEQRYGGGFYSTQDTINAIEGLTEYSLLVKQLRLSMDIDVSYKHKGALHNYKMTDKNFLGRPVEVLLNDDLIVSTGFGSGLATVHVTTVVHKTSTSEEVCSFYLKIDTQDIEASHYRGYGNSDYKRIVACASYKPSREESSSGSSHAVMDISLPTGISANEEDLKALVEGVDQLFTDYQIKDGHVILQLNSIPSSDFLCVRFRIFELFEVGFLSPATFTVYEYHRPDKQCTMFYSTSNIKIQKVCEGAACKCVEADCGQMQEELDLTISAETRKQTACKPEIAYAYKVSITSITVENVFVKYKATLLDIYKTGEAVAEKDSEITFIKKVTCTNAELVKGRQYLIMGKEALQIKYNFSFRYIYPLDSLTWIEYWPRDTTCSSCQAFLANLDEFAEDIFLNGC。
本文所用的术语“C5”是指具有SEQ ID NO:5的人类C5蛋白以及与其基本相同的序列。优选地,所述序列是SEQ ID NO:5。
内膜层中HPT的存在和累积与其在促进从红细胞(RBC)释放的游离血红蛋白的清除中的抗氧化作用一致;然而,以前还没有记载HPT在斑块形成的最早阶段的累积。在这点上,最近已经显示了早期动脉粥样硬化斑块中存在氧化还原活性铁、血红蛋白和血型糖蛋白A,这暗示了内膜RBC浸润作为内膜氧化的初始触发物之一(Delbosc S等人,2017)。
几项人类研究已经表明HPT 2-2表型可能与2型糖尿病中的CVD有关(Levy AP等人,2002;Levy AP等人,2004)。先前已经在CAD患者中观察到增加的HPT水平(Lee CW等人,2013)并且预测CV事件(Holme I等人,2009)。HPT被认为是一种急性期蛋白,并且与这种类别的其它蛋白质(如CRP、纤维蛋白原和血清-淀粉样蛋白)一样,已经被用作炎症的标志物。这些标志物单独或组合地改善了对严重CV事件如急性心肌梗塞和缺血性中风的预测(Holme I等人,2009;Engstrom G等人,2002;Holme I等人,2010;Brea D等人,2009;Sabatine MS等人,2007)。然而,这些蛋白质还检测其它炎症相关疾病;例如,HPT和纤维蛋白原的相似增加发生在患有肾功能障碍或晚期CV疾病的患者中,反映了这些病况中共有的炎症事件(Luczak M等人,2011)。此外,最近对581名患者的急性期蛋白与CV结果之间关联的研究发现HPT与冠状动脉斑块特点或临床事件之间没有关联(Battes LC等人,2014)。在发现蛋白质组学研究中,发现炎症标志物SAA-1和CRP在患有稳定的动脉粥样硬化或急性冠状动脉综合征的患者中增加,但没有检测到HPT水平的变化(Kristensen LP等人,2014)。我们的结果显示这些急性期蛋白与斑块厚度或CACS没有关联。这些结果表明HPT血浆水平不严格跟踪炎症标志物的行为。
人类触珠蛋白的规范序列被称为SEQ ID NO:9(UniProtKB登录号P00738;这是1986年7月21日第1版的序列):
MSALGAVIALLLWGQLFAVDSGNDVTDIADDGCPKPPEIAHGYVEHSVRYQCKNYYKLRTEGDGVYTLNDKKQWINKAVGDKLPECEADDGCPKPPEIAHGYVEHSVRYQCKNYYKLRTEGDGVYTLNNEKQWINKAVGDKLPECEAVCGKPKNPANPVQRILGGHLDAKGSFPWQAKMVSHHNLTTGATLINEQWLLTTAKNLFLNHSENATAKDIAPTLTLYVGKKQLVEIEKVVLHPNYSQVDIGLIKLKQKVSVNERVMPICLPSKDYAEVGRVGYVSGWGRNANFKFTDHLKYVMLPVADQDQCIRHYEGSTVPEKKTPKSPVGVQPILNEHTFCAGMSKYQEDTCYGDAGSAFAVHDLEEDTWYATGILSFDKSCAVAEYGVYVKVTSIQDWVQKTIAEN。
本文所用的术语“HPT”是指具有SEQ ID NO:9的人类触珠蛋白以及与其基本相同的序列。优选地,所述序列是SEQ ID NO:9。
先前已经在动脉粥样化的富含脂质的核心中发现了HEP2(Rau JC等人,2009),但尚未在早期斑块中描述。HEP2的表达降低与动脉粥样硬化的加重相关(Kanagawa Y等人,2001;Takamori N等人,2004),这大概是由于其作为凝血酶抑制剂的作用。类似地,血浆HEP2活性与动脉疾病的患病率呈负相关(Aihara K等人,2009),已经显示具有高水平HEP2的个体具有较少的动脉粥样硬化(Aihara K等人,2004),以及HEP2被认为对血管和心脏重塑起保护作用(Aihara K等人,2009;Ikeda Y等人,2012)。因此,从先前的研究中无法预期我们的发现,即HEP2在亚临床动脉粥样硬化中增加。
人类肝素辅因子2(HEP2)的规范序列被称为SEQ ID NO:10(UniProtKB登录号P05546;这是1991年11月1日第3版的序列):
MKHSLNALLIFLIITSAWGGSKGPLDQLEKGGETAQSADPQWEQLNNKNLSMPLLPADFHKENTVTNDWIPEGEEDDDYLDLEKIFSEDDDYIDIVDSLSVSPTDSDVSAGNILQLFHGKSRIQRLNILNAKFAFNLYRVLKDQVNTFDNIFIAPVGISTAMGMISLGLKGETHEQVHSILHFKDFVNASSKYEITTIHNLFRKLTHRLFRRNFGYTLRSVNDLYIQKQFPILLDFKTKVREYYFAEAQIADFSDPAFISKTNNHIMKLTKGLIKDALENIDPATQMMILNCIYFKGSWVNKFPVEMTHNHNFRLNEREVVKVSMMQTKGNFLAANDQELDCDILQLEYVGGISMLIVVPHKMSGMKTLEAQLTPRVVERWQKSMTNRTREVLLPKFKLEKNYNLVESLKLMGIRMLFDKNGNMAGISDQRIAIDLFKHQGTITVNEEGTQATTVTTVGFMPLSTQVRFTVDRPFLFLIYEHRTSCLLFMGRVANPSRS。
本文所用的术语“HEP2”是指具有SEQ ID NO:10的人类HEP2蛋白以及与其基本相同的序列。优选地,所述序列是SEQ ID NO:10。
在特定的实施方案中,用于本发明的筛选、诊断和/或监测的方法包括在步骤a)中测定一种或多种生物标志物的蛋白质表达水平,所述生物标志物包含以下或由以下组成:
i.PIGR和/或IGHA2;以及
ii.任选地,选自APOA、HPT、HEP2、ITIH1和C5的一种、两种、三种、四种或五种生物标志物。
优选地,步骤a)包括测定PIGR和/或IGHA2以及选自APOA、HPT、HEP2、ITIH1和C5的一种、两种或三种生物标志物的表达水平。因此,在优选的实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,步骤a)中的所述一种或多种生物标志物是包含以下或由以下组成的多个生物标志物:
a.PIGR和/或IGHA2和APOA;
b.PIGR和/或IGHA2和HPT;
c.PIGR和/或IGHA2和HEP2;
d.PIGR和/或IGHA2和C5;
e.PIGR和/或IGHA2和ITIH1;
f.PIGR和/或IGHA2、APOA和HPT;
g.PIGR和/或IGHA2、APOA和HEP2;
h.PIGR和/或IGHA2、APOA和C5;
i.PIGR和/或IGHA2、APOA和ITIH1;
j.PIGR和/或IGHA2、HPT和HEP2;
k.PIGR和/或IGHA2、HPT和C5;
l.PIGR和/或IGHA2、HPT和ITIH1;
m.PIGR和/或IGHA2、HEP2和C5;
n.PIGR和/或IGHA2、HEP2和ITIH1;
o.PIGR和/或IGHA2、APOA、HPT和C5;
p.PIGR和/或IGHA2、APOA、HPT和ITIH1;
q.PIGR和/或IGHA2、APOA、HEP2和C5;
r.PIGR和/或IGHA2、APOA、HEP2和ITIH1;
s.PIGR和/或IGHA2、HPT、HEP2和C5;
t.PIGR和/或IGHA2、HPT、HEP2和ITIH1;以及
u.PIGR和/或IGHA2、APOA、HPT和HEP2。
在特定的实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,步骤a)中的所述一种或多种生物标志物是包含以下或由以下组成的多个生物标志物:
-PIGR、APOA和ITIH1;或
-PIGR、APOA和C5;或
-IGHA2、APOA和ITIH1;或
-IGHA2、APOA和C5;或
-PIGR、ITIH1和C5;或
-IGHA2、ITIH1和C5。
更优选地,a)中的所述多个生物标志物包含PIGR和/或IGHA2;还包含两种生物标志物,其为APOA以及HPT、HEP2、ITIH1或C5中的至少一种。因此,在另一个实施方案中,任选地与本文所述的任何实施方案或特征组合,所述多个生物标志物包含以下或由以下组成:
-IGHA2、APOA以及HPT、HEP2、ITIH1或C5中的至少一种;或者
-PIGR、APOA以及HPT、HEP2、ITIH1或C5中的至少一种。
甚至更优选地,a)中的所述多个生物标志物包含以下或由以下组成:
-IGHA2、APOA和HPT;或
-PIGR、APOA和HPT。
在另外的实施方案中,a)中的所述多个生物标志物包含以下或由以下组成:PIGR、IGHA2、APOA以及HPT、HEP2、ITIH1或C5中的至少一种。优选地,a)中的所述多个生物标志物包含选自以下的多个生物标志物或由其组成:
(i)PIGR、IGHA2、APOA、ITIH1和C5;
(ii)PIGR、IGHA2、APOA、HPT和HEP2;
(iii)PIGR、IGHA2、APOA、HPT和ITIH1;
(iv)PIGR、IGHA2、APOA、HPT和C5;
(v)PIGR、IGHA2、APOA、HEP2和ITIH1;以及
(vi)PIGR、IGHA2、APOA、HEP2和C5。
替代实施方案包括在步骤a)中测定一种或多种生物标志物的表达水平,所述生物标志物包含以下或由以下组成:
i.至少ITIH1;以及
ii.任选地,选自APOA、HPT、HEP2、C5、PIGR和IGHA2的一种、两种、三种、四种、五种或六种生物标志物。
优选地,a)中的所述一种或多种生物标志物是多个生物标志物,其包含ITIH1以及选自APOA、HPT、HEP2、C5、PIGR和IGHA2的一种或两种生物标志物。因此,在优选的实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,所述多个生物标志物包含以下或由以下组成:
-ITIH1和APOA;或
-ITIH1和PIGR;或
-ITIH1和IGHA2;或
-ITIH1和C5;或
-ITIH1和HPT;或
-ITIH1和HEP2;或
-ITIH1、APOA和PIGR;或
-ITIH1、APOA和IGHA2;或
-ITIH1、APOA和C5;或
-ITIH1、APOA和HPT;或
-ITIH1、APOA和HEP2;或
-ITIH1、PIGR和IGHA2;或
-ITIH1、PIGR和C5;或
-ITIH1、PIGR和HPT;或ITIH1、PIGR和HEP2;或
-ITIH1、IGHA2和C5;或
-ITIH1、IGHA2和HPT;或
-ITIH1、IGHA2和HEP2;或
-ITIH1、C5和HPT;或
-ITIH1、C5和HEP2;或
-ITIH1、HPT和HEP2。
更优选地,a)中的所述多个生物标志物包含ITIH1和两种生物标志物,所述两种生物标志物由(i)APOA;以及(ii)PIGR、IGHA2、HPT、HEP2或C5中的至少一种组成。
另外的替代实施方案包括在步骤a)中测定一种或多种生物标志物的表达水平,所述生物标志物包含以下或由以下组成:
i.至少HPT;以及
ii.任选地,选自APOA、HEP2、C5、ITIH1、PIGR和IGHA2的一种、两种、三种、四种、五种或六种生物标志物。
优选地,a)中的所述多个生物标志物包含HPT以及选自APOA、HEP2、C5、ITIH1、PIGR和IGHA2的一种或两种生物标志物。因此,在优选的实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,所述多个生物标志物包含以下或由以下组成:
-HPT和APOA;或
-HPT和PIGR;或
-HPT和IGHA2;或
-HPT和C5;或
-HPT和ITIH1;或
-HPT和HEP2;
-HPT、APOA和PIGR;或
-HPT、APOA和IGHA2;或
-HPT、APOA和C5;或
-HPT、APOA和ITIH1;或
-HPT、APOA和HEP2;或
-HPT、PIGR和IGHA2;或
-HPT、PIGR和C5;或
-HPT、PIGR和ITIH1;或
-HPT、PIGR和HEP2;或
-HPT、IGHA2和C5;或
-HPT、IGHA2和ITIH1;或
-HPT、IGHA2和HEP2;或
-HPT、C5和ITIH1;或
-HPT、C5和HEP2;或
-HPT、ITIH1和HEP2。
更优选地,a)中的所述多个生物标志物包含HPT和两种生物标志物,所述两种生物标志物由(i)APOA;以及(ii)PIGR、HEP2、IGHA2、C5或ITIH1中的至少一种组成。
另外的替代实施方案包括在步骤a)中测定一种或多种生物标志物的表达水平,所述生物标志物包含以下或由以下组成:
i.至少APOA;以及
ii.任选地,选自ITIH1、HPT、HEP2、C5、PIGR和IGHA2的一种、两种、三种、四种、五种或六种生物标志物。
优选地,a)中的所述一种或多种生物标志物是多个生物标志物,其包含APOA以及选自ITIH1、HPT、HEP2、C5、PIGR和IGHA2的一种或两种生物标志物。因此,在优选的实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,所述多个生物标志物包含以下或由以下组成:
-APOA和ITIH1;或
-APOA和PIGR;或
-APOA和IGHA2;或
-APOA和C5;或
-APOA和HPT;或
-APOA和HEP2;或
-APOA、ITIH1和PIGR;或
-APOA、ITIH1和IGHA2;或
-APOA、ITIH1和C5;或
-APOA、ITIH1和HPT;或
-APOA、ITIH1和HEP2;或
-APOA、PIGR和IGHA2;或
-APOA、PIGR和C5;或
-APOA、PIGR和HPT;或
-APOA、PIGR和HEP2;或
-APOA、IGHA2和C5;或
-APOA、IGHA2和HPT;或
-APOA、IGHA2和HEP2;或
-APOA、C5和HPT;或
-APOA、C5和HEP2;或
-APOA、HPT和HEP2。
更优选地,a)中的所述多个生物标志物包含APOA和两种生物标志物,所述两种生物标志物由以下组成:(i)HPT;以及(ii)PIGR、IGHA2、HEP2、ITIH1或C5中的至少一种。
另外的替代实施方案包括在步骤a)中测定一种或多种生物标志物的表达水平,所述生物标志物包含以下或由以下组成:
i.至少HEP2;以及
ii.任选地,选自APOA、HPT、C5、ITIH1、PIGR和IGHA2的一种、两种、三种、四种、五种或六种生物标志物。
优选地,a)中的所述多个生物标志物包含HEP2和选自APOA、HPT、C5、ITIH1、PIGR和IGHA2的一种或两种生物标志物。因此,在优选的实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,所述多个生物标志物包含以下或由以下组成:
-HEP2和APOA;或
-HEP2和PIGR;或
-HEP2和IGHA2;或
-HEP2和C5;或
-HEP2和ITIH1;或
-HEP2和HPT;
-HEP2、APOA和PIGR;或
-HEP2、APOA和IGHA2;或
-HEP2、APOA和C5;或
-HEP2、APOA和ITIH1;或
-HEP2、APOA和HPT;或
-HEP2、PIGR和IGHA2;或
-HEP2、PIGR和C5;或
-HEP2、PIGR和ITIH1;或
-HEP2、PIGR和HPT;或
-HEP2、IGHA2和C5;或
-HEP2、IGHA2和ITIH1;或
-HEP2、IGHA2和HPT;或
-HEP2、C5和ITIH1;或
-HEP2、C5和HPT;或
-HEP2、ITIH1和HPT。
更优选地,a)中的所述多个生物标志物包含HEP2和两种生物标志物,所述两种生物标志物由以下组成:(i)APOA;以及(ii)PIGR、HPT、IGHA2、C5或ITIH1中的至少一种。
本文所用的术语“样品”或“生物样品”是指从对象分离的生物材料。生物样品可以包含适于检测所需生物标志物的任何生物材料,并且可以包含来自对象的细胞和/或非细胞材料。样品可以分离自任何合适的生物组织或流体,诸如例如血液,血浆,血清,脑脊液(CSF),尿液,羊水,淋巴液,呼吸道、肠道、泌尿生殖道的外分泌物,眼泪,唾液,白细胞。优选地,在本发明的方法中用于测定蛋白质标志物水平的样品是可以使用最小侵入性程序获得的样品。在优选的实施方案中,样品是血液、血浆或血清样品。优选地,该生物样品是血浆。
这些类型的样品在临床实践中常规使用,并且本领域技术人员知道如何鉴定用于其获得和保存的最适当的手段。一旦已经获得样品,可以将其新鲜使用,可以使用适当的手段将其冷冻、冻干或保存。
本文所用的表述“测定标志物的水平”是指确定样品中生物标志物的绝对或相对量或浓度。用于测定来自测试样品的单独生物标志物的水平的技术是本领域技术人员众所周知的,并且本发明不受评估组分所采用的手段的限制。
用于定量蛋白质表达的方法是本领域众所周知的。用于测定给定蛋白质水平的合适方法包括但不限于下文所述的那些方法。在本发明的方法中测定蛋白质表达水平的优选方法是免疫测定。用于定量目的蛋白的多种类型的免疫测定是本领域技术人员已知的。这些方法基于亲和试剂的使用,所述亲和试剂可以是特异性结合靶蛋白或其片段的任何抗体或其它配体,其中所述亲和试剂优选是标记的。例如,亲和试剂可以是酶促标记的,或者用放射性同位素或用荧光剂标记。
亲和试剂可以是特异性结合靶蛋白或其片段的任何抗体或配体。亲和配体可以包括蛋白质、肽、核酸或肽适配体以及其它靶标特异性蛋白质支架,如抗体模拟物。可以例如通过用本发明的蛋白质或其片段免疫宿主来产生针对本发明方法中使用的蛋白质标志物的特异性抗体。同样地,可以由筛选合成的肽文库产生针对本发明方法中使用的蛋白质标志物具有特异性的肽。
蛋白质印迹或免疫印迹技术允许比较由电泳凝胶分离的蛋白质(例如,通过3-D结构的天然蛋白质或通过多肽长度的变性蛋白质)的相对丰度。免疫印迹技术使用抗体(或相关技术中的其它特异性配体)来鉴定多种不相关蛋白种类中的靶蛋白。它们涉及通过抗原-抗体(或蛋白质-配体)特异性反应来鉴定蛋白靶标。蛋白质通常通过电泳分离并转移到聚合材料(通常为硝化纤维素、尼龙或聚偏二氟乙烯)的薄片上。斑点印迹和狭缝印迹是简化的程序,其中蛋白质样品不通过电泳分离而是直接固定在膜上。
传统上,溶液中蛋白质的定量是通过在固体支持物上的免疫测定进行的。所述免疫测定可以是例如酶联免疫吸附测定(ELISA)、荧光免疫吸附测定(FIA)、化学发光免疫测定(CIA)或放射免疫测定(RIA)、酶放大免疫测定、固相放射免疫测定(SPROA)、荧光偏振(FP)测定、荧光共振能量转移(FRET)测定、时间分辨荧光共振能量转移(TR-FRET)测定、表面等离子体共振(SPR)测定。特别涵盖了以上任一种的多重和任何下一代版本。在特定的实施方案中,所述免疫测定是ELISA测定或其任何多重形式。
可以用于定量溶液中蛋白质的其它方法是基于质谱(mass spectrometry,MS),也称为质谱分析(mass spectroscopy)的技术。本文所用的术语“基于质谱(MS)的方法”是指单独的质谱或者与其它检测或分离方法偶联(coupled to)的质谱,包括气相色谱与质谱结合、液相色谱与质谱结合、超临界流体色谱与质谱结合、超高效液相色谱与质谱结合、MALDI与质谱结合、离子喷雾光谱与质谱结合、毛细管电泳与质谱结合、NMR结合质谱和IR与质谱结合。这些基于MS的方法可以包括单个MS或串联MS。在另一个特定的实施方案中,通过液相色谱-串联质谱联用(LC-MS/MS)测定蛋白质表达水平。
质谱仪通过将分析物分子转换为带电(电离)状态,随后基于它们的质荷比(m/z)对电离过程期间产生的离子和任何碎片离子进行分析来操作。几种不同的技术可用于电离和离子分析,产生了具有这两个过程的不同组合的许多不同类型的质谱仪。一方面,离子源的实例包括电喷雾电离源、大气压力化学电离源、大气压力光电离或基质辅助激光解吸电离(MALDI)。另一方面,质谱仪分析器可以是但不限于四极杆分析器,飞行时间(TOF)分析器,离子阱分析器,轨道阱分析器或混合分析器,如混合四极杆飞行时间(QTOF)分析器、混合四极杆轨道阱分析器、混合离子阱-轨道阱分析器、混合三重四极杆线性离子阱分析器或三杂交四极杆-离子阱-轨道阱分析器。在优选的实施方案中,通过使用混合四极杆-轨道阱分析器来测定蛋白质标志物水平。
在MS分析中可以使用内标,因为它能够校正样品制备过程中的任何损失或低效率或者电离效率的改变,例如由于离子阻抑引起的那些。分析物的稳定或同重元素同位素形式是理想的内标,因为它们具有几乎相同的化学性质,但在MS期间容易区分。在优选的实施方案中,任选地与以上或以下描述的一个或多个实施方案组合,通过基于MS的方法使用同位素/同重元素标记形式的蛋白质标志物作为内标进行蛋白质标志物水平的测定。另外或者可选地,萃取溶剂可以掺有在未掺有生物样品中未检测到的化合物。
如实施例所示(参见表5和6),IGHG1和IGHG2也是亚临床动脉粥样硬化的独立预测因子。特别地,已经显示这些在疾病存在下降低。因此,本发明的方法还可以包括:
a)测定所述生物样品中IGHG1和/或IGHG2的蛋白质表达水平,
b)将所述生物标志物的水平与参考值进行比较,
c)其中当对象样品中IGHG1和/或IGHG2的水平相对于相应的参考值降低时,表明亚临床动脉粥样硬化。
另外,IGHA2水平可以相对于免疫球蛋白重链恒定区α1(IGHA1)、免疫球蛋白重链恒定区γ1(IGHG1)、免疫球蛋白重链恒定区γ2(IGHG2)或其组合中的任一种的水平来表达。优选地,IGHA2水平相对于IGHA1水平或IGHG1和IGHG2的平均水平表达。
人免疫球蛋白重链恒定区α1(IGHA1)的规范序列被称为SEQ ID NO:6(UniProtKB登录号P01876-1;这是1991年2月1日的第2版序列):
ASPTSPKVFPLSLCSTQPDGNVVIACLVQGFFPQEPLSVTWSESGQGVTARNFPPSQDASGDLYTTSSQLTLPATQCLAGKSVTCHVKHYTNPSQDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPRLSLHRPALEDLLLGSEANLTCTLTGLRDASGVTFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAEPWNHGKTFTCTAAYPESKTPLTATLSKSGNTFRPEVHLLPPPSEELALNELVTLTCLARGFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTFAVTSILRVAAEDWKKGDTFSCMVGHEALPLAFTQKTIDRLAGKPTHVNVSVVMAEVDGTCY。
本文所用的术语“IGHA1”是指具有SEQ ID NO:6的人IGHA1蛋白以及与其基本相同的序列。优选地,所述序列是SEQ ID NO:6。
人免疫球蛋白重链恒定区γ1(IGHG1)的规范序列被称为SEQ ID NO:7(UniProtKB登录号P01857-1;这是1986年7月21日的第1版序列):
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK。
本文所用的术语“IGHG1”是指具有SEQ ID NO:7的人IGHG1蛋白以及与其基本相同的序列。优选地,所述序列是SEQ ID NO:7。
人免疫球蛋白重链恒定区γ2(IGHG2)的规范序列被称为SEQ ID NO:8(UniProtKB登录号P01859-1;这是2008年12月16日的第2版序列):
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK。
本文所用的术语“IGHG2”是指具有SEQ ID NO:8的人IGHG2蛋白以及与其基本相同序列。优选地,所述序列是SEQ ID NO:8。
本申请的发明人还发现,在PESA-V1中,IGHG1、IGKC和IGLC2随着斑块厚度而降低,然而IGHA1、IGHG3、IGHG4和IGHM不受影响,在PESA-V2中保持这些可检测到的变化(图3A)。因此,所呈现的数据支持了体液免疫应答在动脉粥样硬化的早期阶段中的作用(Tsiantoulas D等人,2014),并且还表明存在Ig类别转换。已经提出与自身免疫疾病中B细胞发育相关的两种因子BAFF(B细胞活化因子)和APRIL(增殖诱导配体)在IgA类别转换中的作用(Kaneko T等人,2014),证据表明BAFF在指导IgA1转换和APRIL在指导IgA2转换中的作用(Litinskiy MB等人,2002)。因此,可以想象,IgA类别转换是通过被提出在动脉粥样硬化期间发生的特定B细胞亚群的差异活化触发的(Tsiantoulas D等人,2014)。
在步骤(b)中,本发明的筛选和/或诊断方法包括将蛋白质标志物的水平与参考值进行比较。
本文所用的术语“参考值”涉及用作评价从对象收集的样品获得的值或数据的参考的预定标准。该“参考值”也可以被称为“截止值”或“阈值”。
参考值或参考水平可以是绝对值、相对值、具有上限或下限的值、一系列值、平均值(average value)、中值、均值(mean value)或者与特定对照或基线值相比的值。参考值可以基于单个样品值,或者可以基于大量样品,例如来自实足年龄匹配组的对象群体,或者基于包括或排除要测试的样品的样品池。
蛋白质标志物的表达水平可以用于计算与参考值相比的组合评分。组合评分是根据给定的数学公式或算法获得的值,其中在本发明的方法中使用的每种蛋白质标志物的表达值是所述数学算法的变量。在特定的实施方案中,当计算组合评分时,这与PIGR、IGHA2、APOA、HPT、HEP2、ITIH1和C5中一种或多种的表达水平成比例,其中评分越高,亚临床动脉粥样硬化的可能性越高。
此外,本发明第一方面的方法中的步骤(c)包括根据与参考值的比较将对象分类为患有亚临床动脉粥样硬化或呈现患有亚临床动脉粥样硬化的高可能性,其中当对象样品中PIGR、IGHA2、APOA、HPT、HEP2、ITIH1和/或C5的水平相对于相应的参考值增加时,表明亚临床动脉粥样硬化。
当生物标志物水平的值高于参考值时,所述生物标志物水平被认为是“增加的”。优选地,当生物标志物水平(或组合评分)比参考值高至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%,至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少100%、至少110%、至少120%、至少130%、至少140%、至少150%或更多时,其被认为高于参考值。
同样地,当生物标志物水平的值低于参考值时,所述生物标志物水平被认为是“降低的”。优选地,当生物标志物水平(或组合评分)比参考值低至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少100%、至少110%、至少120%、至少130%、至少140%、至少150%或更多时,其被认为低于参考值。
可选地或另外,对象具有相对于本文所述的参考值大于约1.1、1.2、1.3、1.4、1.5、2、3、4、5、6、7、8、9、10、15或20倍的水平偏差。
如本领域技术人员所理解的,本发明的方法并不要求在100%的分析样品中是正确的。然而,它需要正确地分类统计上显著量的分析样品。统计上显著的量可以是本领域技术人员通过使用统计检验获得的不同统计显著性度量确立的;所述统计显著性度量的说明性非限制性实例包括确定置信区间、确定p值等。优选的置信区间是至少90%、至少95%、至少97%、至少98%、至少99%。p值优选小于0.1、小于0.05、小于0.01、小于0.005或小于0.0001。本发明的教导优选允许正确地分类所分析的测定组或群体的至少60%、至少70%、至少80%或至少90%的对象。
还应注意,通过另外考虑患者的生化参数和/或临床特征(例如,年龄、性别、抽烟和/或其它心血管风险因素),如传统的心血管风险评分中包括的那些,还可以提高本发明方法的准确性。
在特定的实施方案中,任选地与本文所述的一个或多个实施方案或特征组合,根据本发明第一方面的方法还包括进行传统的心血管风险评分。通常,风险评分包括对象的生化和生理学测定,以及其它临床和/或生活方式特点。优选地,所述传统的心血管风险评分选自10-y FHS或30-y FHS(Kannel等人,1979;Splansky等人,2007)、ICHS(Fernández-Alvira等人,2017)和BEWAT(Fernández-Alvira等人,2017)评分,更优选地,其中所述心血管风险评分是10-y FHS。
使用适当的数学组合,优选使用多变量逻辑回归模型,可以将所述风险评分与PIGR、IGHA2、APOA、HPT、HEP2、ITIH1和/或C5(包括如本文以上描述的它们的任意组合)的蛋白质测量组合。
在特定的实施方案中,任选地与本文所述的任何实施方案或特征组合,所述方法优选是用于亚临床动脉粥样硬化的筛选和/或诊断的方法,并且当进行传统的心血管风险评分时,在从被分类为低风险的对象分离的样品中进行生物标志物测量。例如,在弗雷明汉风险评分(FHS-10y)的帮助下,可以计算10年的冠心病(CHD)风险百分比。具有低风险的个体在10年时具有10%或更少的CHD风险,具有中等风险的个体在10年时具有10-20%的CHD风险,以及具有高风险的个体在10年时具有20%或更多的CHD风险。然而,应记住,这些分类是任意的。
此外,本发明第一方面的方法可以包括另外进行体内成像研究。这可以包括但不限于动脉粥样硬化斑块的存在和形态的2/3维血管超声分析以及冠状动脉钙化的计算机断层扫描分析。优选地,在选择用于在步骤c)中呈现表明动脉粥样硬化的生物标志物水平的那些对象中进行另外的体内成像研究。
本发明的方法或其任何步骤可以由计算机实现。因此,本发明的另一方面涉及计算机实现的方法,其中所述方法是本文所公开的任何方法或其任何组合。
注意,能够实现本发明的任何方法或用于实现这些方法中的任一种或其任何组合的任何计算机程序也构成本发明的一部分。该计算机程序通常可直接加载到数字计算机的内部存储器中,包括软件代码部分,用于当所述产品在计算机上运行时,执行将来自对象的一个或多个生物样品的如本发明所述的蛋白质标志物的水平与参考值进行比较,以及确定亚临床动脉粥样硬化的存在或患有亚临床动脉粥样硬化可能性的步骤。
还应注意,包括任何装置或设备作为本说明书的组成部分,所述装置或设备包括用于执行本发明的任何方法或其任何组合的步骤,或者携带能够实现本发明的任何方法或其任何组合的计算机程序的装置。
本发明的方法还可以包括将方法结果存储在数据载体中,优选地,其中所述数据载体是计算机可读介质。本发明还涉及其上存储有本发明的计算机程序或本发明的任何方法的结果的计算机可读存储介质。如本文所用,“计算机可读介质”可以是任何设备,其可以包括、存储、通信、传播或传送本发明方法的测定结果。介质可以是电、磁、光、电磁、红外或半导体系统(或设备或装置)或传播介质。
在第二方面,本发明提供了用于治疗患有亚临床动脉粥样硬化的对象的方法,其中所述方法包括:
a.通过如本文所定义的用于筛选、诊断和/或监测的方法鉴定患有亚临床动脉粥样硬化的对象;
b.向所述患者施用治疗有效量的用于预防/减少动脉粥样硬化斑块的合适治疗。
这些可以包括用于降低HDL胆固醇水平或总甘油三酯水平;和/或增加血浆中HDL胆固醇水平的治疗。他汀类药物是目前可用于降低血液中LDL水平的治疗上最有效的药物。也已知他汀类药物能提高HDL胆固醇水平和降低总甘油三酯水平。认为他汀类药物通过竞争性抑制3-羟基-3-甲基-戊二酰-辅酶A还原酶(“HMG-CoA还原酶”)来破坏肝脏中胆固醇和其它甾醇的生物合成。HMG-CoA还原酶催化HMG-CoA转化成甲羟戊酸,甲羟戊酸是胆固醇生物合成中的定速步骤。因此,其抑制导致肝脏中胆固醇的形成速率降低。他汀类药物是本领域众所周知的,并且这些包括例如普伐他汀、辛伐他汀、洛伐他汀、氟伐他汀、阿托伐他汀和罗苏伐他汀。
试剂盒和试剂盒在本发明方法中的用途
在另一方面,本发明涉及用于测定从对象分离的生物样品中如本文所述的一种或多种蛋白质标志物的水平的试剂盒。试剂盒还可以含有指示可以如何使用试剂盒内的材料的说明书。
术语“试剂盒”或“测试试剂盒”表示分析所需的试剂和佐剂的组合。尽管在大多数情况下测试试剂盒由几个单元组成,但也可以使用单件式分析元件,其同样必须被认为是测试试剂盒。
在特定的实施方案中,本发明的试剂盒包含足以测定选自以下的一种或多种标志物的蛋白质表达水平的试剂:PIGR、IGHA2、APOA、HPT、HEP2、ITIH1和C5。
这些试剂可用于使用如上文所述的任何合适的方法测定靶蛋白标志物的表达水平。例如,所述蛋白质标志物的水平的测定可以通过使用如本发明第一方面所述的亲和试剂(例如,通过免疫测定)来进行。
在特定的实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,所述试剂盒包含:
a.用于测定PIGR或IGHA2中至少一种(优选PIGR和IGHA2)的蛋白质表达水平的试剂(例如,针对PIGR或IGHA2中至少一种的亲和试剂);
b.任选地,用于测定APOA、HPT、HEP2、ITIH1和C5中的一种、两种、三种、四种或五种的蛋白质表达水平的试剂(例如,针对APOA、HPT、HEP2、ITIH1和C5中的一种、两种、三种、四种或五种的亲和试剂);
c.任选地,还包含使用所述试剂测定从对象分离的生物样品中所述蛋白质表达水平的说明书。
在优选的实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,所述试剂盒包含:
a.用于测定PIGR或IGHA2中至少一种的蛋白质表达水平的试剂(例如,针对PIGR或IGHA2中至少一种的亲和试剂)(优选地,用于测定PIGR的蛋白质表达水平的试剂以及用于测定IGHA2的蛋白质表达水平的试剂);
b.用于测定APOA的蛋白质表达水平的试剂(例如,针对APOA的亲和试剂);以及
c.用于测定HPT、HEP2、ITIH1或C5中至少一种的蛋白质表达水平的试剂(例如,针对HPT、HEP2、ITIH1或C5中至少一种的亲和试剂);
d.任选地,还包含使用所述试剂测定从对象分离的生物样品中所述蛋白质表达水平的说明书。
在替代实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,所述试剂盒包含:
a.用于测定ITIH1的蛋白质表达水平的试剂(例如,针对ITIH1的亲和试剂);
b.任选地,用于测定选自APOA、HPT、HEP2、C5、PIGR和IGHA2中的一种、两种、三种、四种、五种或六种生物标志物的蛋白质表达水平的试剂(例如,针对选自APOA、HPT、HEP2、C5、PIGR和IGHA2中的一种、两种、三种、四种、五种或六种生物标志物的亲和试剂);
c.任选地,还包含使用所述试剂测定从对象分离的生物样品中所述蛋白质表达水平的说明书。
在优选的实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,所述试剂盒包含:
a.用于测定ITIH1的蛋白质表达水平的试剂(例如,针对ITIH1的亲和试剂);
b.用于测定APOA的蛋白质表达水平的试剂(例如,针APOA的亲和试剂);以及
c.用于测定PIGR、HPT、HEP2、IGHA2或C5中至少一种的蛋白质表达水平的试剂(例如,针对PIGR、HPT、HEP2、IGHA2或C5中至少一种的亲和试剂);
d.任选地,还包含使用所述试剂测定从对象分离的生物样品中所述蛋白质表达水平的说明书。
在另一个替代的实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,所述试剂盒包含:
a.用于测定HPT的蛋白质表达水平的试剂(例如,针对HPT的亲和试剂);
b.任选地,用于测定选自APOA、ITIH1、HEP2、C5、PIGR和IGHA2的一种、两种、三种、四种、五种或六种生物标志物的蛋白质表达水平的试剂(例如,针对选自APOA、ITIH1、HEP2、C5、PIGR和IGHA2的一种、两种、三种、四种、五种或六种的亲和试剂);
c.任选地,还包含使用所述试剂测定从对象分离的生物样品中所述蛋白质表达水平的说明书。
在优选的实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,所述试剂盒包含:
a.用于测定HPT的蛋白质表达水平的试剂(例如,针对HPT的亲和试剂);
b.用于测定APOA的蛋白质表达水平的试剂(例如,针对APOA的亲和试剂);以及
c.用于测定PIGR、ITIH1、HEP2、IGHA2或C5中至少一种的蛋白质表达水平的试剂(例如,针对PIGR、ITIH1、HEP2、IGHA2或C5中至少一种的亲和试剂);
d.任选地,还包含使用所述试剂测定从对象分离的生物样品中所述蛋白质表达水平的说明书。
在另外的替代实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,所述试剂盒包含:
a.用于测定APOA的蛋白质表达水平的试剂(例如,针对APOA的亲和试剂);
b.任选地,用于测定选自ITIH1、HPT、HEP2、C5、PIGR和IGHA2的一种、两种、三种、四种、五种或六种生物标志物的蛋白质表达水平的试剂(例如,针对选自ITIH1、HPT、HEP2、C5、PIGR和IGHA2的一种、两种、三种、四种、五种或六种生物标志物的亲和试剂);
c.任选地,还包含使用所述试剂测定从对象分离的生物样品中所述蛋白质表达水平的说明书。
在优选的实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,所述试剂盒包含:
a.用于测定APOA的蛋白质表达水平的试剂(例如,针对APOA的亲和试剂);
b.用于测定HPT的蛋白质表达水平的试剂(例如,针对HPT的亲和试剂);以及
c.用于测定PIGR、ITIH1、HEP2、IGHA2或C5中至少一种的蛋白质表达水平的试剂(例如,针对PIGR、ITIH1、HEP2、IGHA2或C5中至少一种的亲和试剂);
d.任选地,还包含使用所述试剂测定从对象分离的生物样品中所述蛋白质表达水平的说明书。
在另一个替代实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,所述试剂盒包含:
a.用于测定HEP2的蛋白质表达水平的试剂(例如,针对HEP2的亲和试剂);
b.任选地,用于测定选自ITIH1、HPT、APOA、C5、PIGR和IGHA2的一种、两种、三种、四种、五种或六种生物标志物的蛋白质表达水平的试剂(例如,针对选自ITIH1、HPT、APOA、C5、PIGR和IGHA2的一种、两种、三种、四种、五种或六种生物标志物的亲和试剂);
c.任选地,还包含使用所述试剂测定从对象分离的生物样品中所述蛋白质表达水平的说明书。
在优选的实施方案中,任选地与本文所述的一个或多个特征或者实施方案组合,所述试剂盒包含:
a.用于测定HEP2的蛋白质表达水平的试剂(例如,针对HEP2的亲和试剂);
b.用于测定APOA的蛋白质表达水平的试剂(例如,针对APOA的亲和试剂);以及
c.用于测定PIGR、ITIH1、HPT、IGHA2或C5中至少一种的蛋白质表达水平的试剂(例如,针对PIGR、ITIH1、HPT、IGHA2或C5中至少一种的亲和试剂);
d.任选地,还包含使用所述试剂测定从对象分离的生物样品中所述蛋白质表达水平的说明书。
待测量的生物标志物和相应试剂(例如亲和试剂)的优选组合如上文针对本发明的第一方面所述。
此外,这些实施方案中的任一个还可以包括以下中的一个或多个:
-用于测定IGHA1的蛋白质表达水平的试剂(例如,针对IGHA1的亲和试剂);
-用于测定IGHG1的蛋白质表达水平的试剂(例如,针对IGHG1的亲和试剂);或
-用于测定IGHG2的蛋白质表达水平的试剂(例如,针对IGHG2的亲和试剂)。
本文所用的术语“针对……的亲和试剂”是指能够特异性结合所述靶蛋白的亲和试剂。各种亲和试剂可以用相同或不同的标签标记。优选地,这些用不同的标签进行标记用于多重分析。
在特定实施方案中,任选地与本文所述的一个或多个实施方案或特征组合,所述亲和试剂是抗体,优选单克隆抗体。亲和试剂可以结合靶蛋白特异的任何线性或构象区域(例如表位)。
与本文所述的蛋白质特异性结合的可商购获得的抗体的示例性/非限制性实例包括以下:
-大鼠单克隆PIGR(7C1,ABCAM)目录号ab170321,
-小鼠抗人IgA2(A9604D2,Southern biotech)目录号9140-01,
-补体C5单克隆抗体(12F3,thermo scientific)目录号HYB029-02-02,
-兔单克隆抗脂蛋白(a)抗体[EPR6474,ABCAM)目录号ab125014,
-ITIH1单克隆抗体(40B10,thermo scientific)目录号LF-MA014,
-IGHA1:小鼠抗人iga1(souther biotech,9130-01)
-IGHG1:小鼠IgG1,κ单克隆(ABCAM,ab81032)
-IGHG2:小鼠抗人-igG2单克隆(SIGMA,I5635)
本文已经描述了可能的免疫测定和亲和试剂。在特定的实施方案中,所述免疫测定是ELISA测定。
在一些实施方案中,试剂盒包含上述针对靶蛋白的亲和试剂和一种或多种辅助试剂。一级亲和试剂(例如一抗)可以用于捕获目的,并且二级亲和试剂(例如二抗)可以用于检测目的。
一级或捕获亲和试剂通常是对靶蛋白特异的单克隆抗体。二级或检测亲和试剂可以是单克隆或多克隆抗体。另外,这些可以来源于任何哺乳动物有机体,包括小鼠、大鼠、仓鼠、山羊、骆驼、鸡、兔等。
可以标记检测亲和试剂。标签或标记物可以是可检测的任何组合物。本领域已知的任何分析方法可以用于测定或检测二级亲和试剂。这些手段包括使用光谱学、化学、光化学、生物化学、免疫化学或光学。标记物可以是,例如,酶(例如,辣根过氧化物酶(HRP)、碱性磷酸酶、β-半乳糖苷酶和ELISA中常用的其它酶)、放射性标记(例如,3H、125I、35S、14C或32P)、化学发光化合物(例如,荧光素和2,3-二氢酞嗪二酮,鲁米诺等)、荧光染料(例如,异硫氰酸荧光素、德克萨斯红、罗丹明等)或本领域已知的任何其它染料。
标记物可以根据本领域众所周知的方法直接或间接(例如,通过结合对,如生物素和亲和素)偶联到检测亲和试剂。如上所述,可以使用多种标签。标记物的选择可以取决于所需的灵敏度、与化合物缀合的容易性、稳定性要求、可利用的仪器或处置规定。
优选地,所述试剂盒包含用一级亲和试剂包被的固体支持物或表面。固体支持物可以包括本领域已知的任何支持物,在其上可以固定本公开内容的蛋白质。在一些实施方案中,所述固体支持物是微量滴定孔板、载物玻璃片(例如,载玻片)、芯片(例如,蛋白质芯片、生物传感器芯片,如Biacore芯片)、微流体盒、比色皿、珠粒(例如,磁珠、珠粒)或树脂。
通常用于免疫测定如固体支持免疫测定的辅助试剂可以包括,例如,本领域技术人员众所周知的固定缓冲液、固定试剂、稀释缓冲液、检测试剂、封闭缓冲液、洗涤缓冲液、检测缓冲液、终止溶液、系统漂洗缓冲液和系统清洁溶液。
本发明的试剂盒的优选特征和实施方案如上文针对本发明的其它方面所定义。
另外,所述蛋白质标志物的水平的测定可以通过基于质谱(MS)的方法进行,并且所述试剂盒可以包含未标记的所述标志物和/或用于通过基于质谱(MS)的方法进行检测的稳定标记的所述标志物,优选地,其中用包含一种或多种稳定同位素的标签来标记标志物。可以并入标签中的同位素原子是重原子,例如13C、15N、18O和/或34S,其可以通过MS区分。
在另外的方面,本发明涉及前述方面的试剂盒在用于如本文所述的亚临床动脉粥样硬化的筛选、诊断和/或监测的方法中的用途。
优选的特征和实施方案如上文针对本发明的其它方面所定义。
预期本文所述的任何特征可以任选地与本发明的任何方法、试剂盒、试剂盒的用途或计算机程序的任何实施方案组合;并且对于这些中的任一个,可以实现在本说明书中讨论的任何实施方案。应理解,本文描述的特定实施方案以说明的方式示出,而不是作为对本发明的限制。在不脱离本发明的范围的情况下,本发明的主要特征可以用于各种实施方案中。
所有出版物和专利申请通过引用并入本文,其程度如同每个单独的出版物或专利申请被明确地和单独地表示为通过引用并入。
词语“一个/一种(a)”或“一个/一种(an)”的使用可以意指“一个/一种(one)”,但它也与“一个或多个/一种或多种”、“至少一个/至少一种”和“一个或多于一个/一种或多于一种”的含义一致。术语“另一个/另一种”的使用也可以指一个或多个/一种或多种。权利要求中术语“或”的使用用于意指“和/或”,除非明确地表示仅指替代方案或者替代方案是互斥的。
如在本说明书和权利要求书中使用的,词语“包含(comprising)”(和“包含”的任何形式,如“包含(comprise)”和“包含(comprises)”)、“具有(having)”(和“具有”的任何形式,如“具有(have)”和“具有(has)”)、“包括(including)”(和“包括”的任何形式,例如“包括(includes)”和“包括(include)”)或“含有(containg)”(和任何形式的“含有”,如“包含(contains)”和“含有(contain)”为包括性的或开放式的且不排除另外的、未提及的要素或方法步骤。术语“包括”也涵盖并明确地公开了术语“由……组成”和“基本上由……组成”。如本文所用,短语“基本上由……组成”将权利要求的范围限制为指定的材料或步骤,以及不会实质上影响所要求保护的发明的基本和新颖特点的那些材料或步骤。如本文所用,短语“由......组成”排除在权利要求中未指定的任何元素、步骤或成分,除了例如通常与该元素或限制相关的杂质之外。
本文所用的术语“或其组合”是指该术语之前所列项目的所有排列和组合。例如,“A、B、C或其组合”旨在包括A、B、C、AB、AC、BC或ABC中的至少一种,并且如果顺序在特定上下文中是重要的,则也包括BA、CA、CB、CBA、BCA、ACB、BAC或CAB。继续这个例子,明确地包括包含一个或多个项目或术语的重复的组合,如BB、AAA、AB、BBC、AAABCCCC、CBBAAA、CABABB等。本领域技术人员将理解,除非从上下文中另外显而易见,通常对任何组合中的项目或术语的数目没有限制。
如本文所用,近似词,如但不限于“约”、“大约”、“近似”是指被理解为当这样修改时不一定是绝对的或完美的但将被认为足够接近本领域普通技术人员保证将条件指定为存在的条件。描述可以变化的程度将取决于可以建立多大的变化,并且本领域普通技术人员仍然认识到修改的特征仍然具有未修改的特征所需的特点和能力。通常,但受制于前面的讨论,通过诸如“约”的近似词修饰的本文的数值可以与所述值相差±1、2、3、4、5、6、7、8、9或10%。因此,术语“约”可以意指其值的指示值±5%,优选其值的指示值±2%,最优选术语“约”精确意指指示值(±0%)。
以下实施例用于说明本发明,而不应解释为限制本发明的范围。
实施例
实施例1-通过定量蛋白质组鉴定亚临床动脉粥样硬化的蛋白质生物标志物-PESA
队列访问1(PESA-v1)
1.1材料和方法
PESA亚队列:对来自476个个体的血浆进行蛋白质组学分析。根据性别、年龄和临床病史对样品进行配对。如前所述(Fernandez-Friera等人,2015;Fernandez-Ortiz等人,2013),对所有PESA个体已经进行了广泛的成像和生化分析。根据亚临床动脉粥样硬化的程度,使用PESA评分(Fernandez-Friera等人,2015)将个体分类为四组:无疾病、病灶化疾病、中间疾病和全身性疾病。
通过多重同重元素标记和数据的定量分析的定量蛋白质组学按照我们实验室中建立的且已经描述的详细方案进行(Burillo等人,2016;Garcia-Marques等人,2016;Gomez-Serrano等人,2016;Latorre-Pellicer等人,2016;Martin-Alonso等人,2015)。鉴定、定量以及统计和系统生物学分析是使用我们实验室中开发的且先前充分描述的模型进行的(Bonzon-Kulichenko等人,2015;Garcia-Marques等人,2016;Jorge等人,2009;Navarro等人,2014;Navarro and Vazquez,2009;Trevisan-Herraz等人,2018,即将出版)。质谱分析在混合四极杆-轨道阱机器(HF Orbitrap,ThermoFisher)中进行。
流行病学分析如下进行。在通过所有其它已知风险因素(例如胆固醇、血压、性别、年龄、LDL和HDL水平)调整之后,使用通过构建多变量线性或逻辑回归模型来预测疾病(就斑块数目、厚度、受累区域的数目或PESA评分而言)的SPSS包,通过分析如上所述测定的定量蛋白质值来进行PESA亚队列中的一组潜在生物标志物的选择。然后进行ROC分析以测量生物标志物组相对于预测心血管风险的现有方法(例如FHS 10年、BEWAT或ICHS评分)的预测能力的增加。
1.2.-在无症状个体中,血浆中的PIGR、APOA和C5水平与动脉粥样硬化病变程度的
关联分析
表1-血浆中的PIGR、APOA和C5水平与平均斑块厚度(通过2D回声测量的)或斑块负荷(通过3D回声测量的)的相关性分析。
该表显示了PIGR、APOA和C5的血浆水平如何与动脉粥样硬化病变程度的两个独立测量中的任一个具有强的相关性,即使在通过常规风险因素进行调整之后。此外,当这三种蛋白质在包括风险因素在内的多变量模型中被一并考虑时,三种蛋白质仍与斑块厚度显著相关。该结果意味着这三种蛋白质彼此独立地与斑块相关。
表2-根据10yFHS,在具有低风险的个体亚群中,血浆中的PIGR、APOA和C5水平与平均斑块厚度(通过2D回声测量的)或斑块负荷(通过3D回声测量的)的相关性分析。
该表显示在多变量模型中一并考虑的PIGR、APOA和C5的水平如何保持它们与动脉粥样硬化病变程度(即使在根据FHS10y具有低风险的个体亚群中)的相关性。这些结果表明,在根据经典风险因素没有心血管风险证据的情况下,这些蛋白质可以独立地且有效地追踪病例中动脉粥样硬化病变的存在。
1.3-在没有或具有动脉粥样硬化病变的情况下,来自人类主动脉的中间层和内膜
层中PIGR、APOA、ITIH1、C5和IGHA2的蛋白水平的分析
图1中所示的数据表明,血浆中选作亚临床动脉粥样硬化的潜在标志物的所有蛋白质,即PIGR、APOA、ITIH1、C5和IGHA2,在中间层中以及主要在内膜层(斑块)中累积,并且随着斑块从脂肪条纹型发展为纤维脂质病变型,累积更高。这种累积可以解释患有亚临床动脉粥样硬化的个体的血浆水平升高(或作为患有亚临床动脉粥样硬化的个体的血浆水平升高的结果)。
1.4-PIGR、APOA和ITH1(C5)血浆水平作为全身性亚临床动脉粥样硬化的独立预测
因子的性能分析
表3-血浆中PIGR、APOA、ITIH1和C5水平作为PESA群体中全身性疾病的预测因子的逻辑回归分析(在PESA评分中的无疾病对比全身性疾病)。
这些数据显示血浆中PIGR、APOA、ITIH1和C5水平中的每一个即使在已知的风险因素被包括在逻辑模型中时也是全身性亚临床动脉粥样硬化的独立预测因子。另外,PIGR、APOA和ITIH1一起也是已知风险评分如10y-FHS、30y-FHS、BEWAT或ICHS存在下的独立预测因子。不希望受理论束缚,在回归分析中,我们观察到C5和ITIH1具有强的协方差,因此它们看起来是相依的。观察到的协方差表明C5和ITIH1可以互换(如果在多变量模型中不考虑ITIH1,则C5以及PIGR和APOA以及任何已知的风险因素表现为独立的预测因子)。
表4-血浆中PIGR、APOA和ITIH1水平作为根据10yFHS或30yFHS具有低风险的个体亚群中的全身性疾病的预测因子的逻辑回归分析。
表4显示PIGR、APOA和ITIH1即使在根据10yFHS具有低风险的个体亚群中也保持它们作为全身性疾病的独立预测因子的能力。该表还显示,PIGR和ITIH1即使在根据30yFHS具有低风险的个体亚群中也保持它们作为全身性疾病的独立预测因子的能力。这些结果表明,在根据经典风险因素没有心血管风险证据的情况下,这些蛋白质可以有效地预测病例中动脉粥样硬化病变的存在。
1.5-与动脉粥样硬化关联的分析以及血浆中IGHA2水平预测全身性动脉粥样硬化
能力的分析
表5-血浆中IGHA1、IGHA2、IGHG1和IGHG2水平与平均斑块厚度(通过2D回声测量的)的相关性分析
该表显示斑块厚度与IGHA2(而不是IGHA1)的增加的丰度和IGHG1或IGHG2的降低的丰度相关,与10yFHS无关。甚至在根据FHS10y具有低风险的个体亚群中也保持与IGHA2的相关性。IGHA2/IGHG1的比值具有比单独的IGHA2甚至更强的相关性。IGHA2/平均值(IGHG1,IGHG2)的比值甚至更好。这些结果表明斑块厚度与Ig同种型转换相关。
表6-血浆中IGHA1、IGHA2、IGHG1和IGHG2水平作为PESA群体中全身性疾病的预测因子的逻辑回归分析(在PESA评分中的无疾病对比全身性疾病)。
该表显示即使在逻辑模型中包括风险评分10yFHS时,血浆中的IGHA2水平(通过或不通过其它Igs校正),而不是IGHA1的水平,也是全身性亚临床动脉粥样硬化的独立预测因子。在具有低风险的人群中保持这种作用。
1.6-生物标志物组作为全身性亚临床动脉粥样硬化的独立预测因子的性能分析
表7-作为PESA群体中全身性疾病的预测因子的几个风险评分和风险因素的接受者操作曲线(ROC)分析(无疾病对比全身性疾病)。
该表显示三个风险评分以及个体风险因素如何能够在没有患病的个体与患有全身性疾病的个体之间产生统计学上显著的区别。
表8-作为PESA群体中全身性疾病的预测因子的PIGR、APOA、ITIH1、C5和IGHA2的接受者操作曲线(ROC)分析(无疾病对比全身性疾病)。
该表显示单独蛋白质中的每一种能够在没有患病的个体与患有全身性疾病的个体之间产生统计学上显著的区别。
表9-含有来自组群PIGR、APOA、ITIH1、C5和IGHA2的三种蛋白质的几个组作为PESA群体中全身性疾病的预测因子的接受者操作曲线(ROC)分析(无疾病对比全身性疾病)。
当与表7中的数据比较时,该表显示可以使用三种蛋白质的组合,其能够以与广泛使用的风险评分相似或比其更好的性能区分没有患病的个体与患有全身性疾病的那些个体。
表10-单独的或与不同蛋白质组组合的10yFHS作为PESA群体中全身性疾病的预测因子的接收者操作曲线(ROC)分析(无疾病对比全身性疾病)。
该表显示向10yFHS中加入含有来自组群PIGR、APOA、ITIH1、C5和IGHA2的几种蛋白质的组产生显著高于单独10yFHS的判别性能(如从AUC值的95%置信区间推断的)。这些结果表明,与目前的标准相比,蛋白质组可以用于显著改善亚临床动脉粥样硬化的预测。
表11-单独的或与不同蛋白质组组合的ICHS作为PESA群体中全身性疾病的预测因子的接收者操作曲线(ROC)分析(无疾病对比全身性疾病)。
该表显示向ICHS中加入含有来自组群PIGR、APOA、ITIH1、C5和IGHA2的几种蛋白质的组产生显著高于单独ICHS的判别性能(如从AUC值的95%置信区间推断的)。这些结果表明,与目前的标准相比,蛋白质组可以用于显著改善亚临床动脉粥样硬化的预测。
表12-单独的或与不同蛋白质组组合的BEWAT评分作为PESA群体中全身性疾病的预测因子的接收者操作曲线(ROC)分析(无疾病对比全身性疾病)。
该表显示向BEWAT评分中加入含有来自组群PIGR、APOA、ITIH1、C5和IGHA2的几种蛋白质的组产生显著高于单独BEWAT的判别性能(如从AUC值的95%置信区间推断的)。这些结果表明,与目前的标准相比,蛋白质组可以用于显著改善亚临床动脉粥样硬化的预测。
实施例2-确认蛋白质丰度变化随时间的稳定性-PESA队列访问2(PESA-v2)&通过
免疫比浊分析来验证获得的生物标志物组
2.1材料和方法
血浆样品。从PESA研究队列(Fernandez-Friera L等人,2015)和AWHS队列(Casasnovas JA等人,2012)中收集血浆样品。对于发现阶段,设计了前瞻性PESA队列内的巢式病例对照研究(PESA-V1)。为了说明潜在的共建(cofounding)和提高效率,将研究限于男性,并且对照与CV风险因素相匹配。首先,在患有广泛的亚临床动脉粥样硬化的参与者中选择222例对象,其被定义为具有3个或更多个受累血管区域的对象。在患有非广泛亚临床动脉粥样硬化的参与者中,以1:1的方式选择对照对象,其被定义为没有或有1个受累血管区域的对象。对照对象与基于年龄(卡尺(caliper):3年)、高血压、血脂异常和糖尿病的病例对象相匹配。在三年后还收集来自相同个体的血浆样品(PESA-V2),除了没有更新对“组学”分析的同意的两个病例及其匹配的对照之外。按照相同的方法在AWHS队列内设计验证集。进行巢式病例对照,其限于男性,并且与年龄、高血压、血脂异常和糖尿病相匹配。在患有广泛的亚临床动脉粥样硬化的参与者中选择220例对象,其被定义为具有3个或更多个受累血管区域的对象。相同数目的对照对象选自患有非广泛亚临床动脉粥样硬化的对照参与者,其被定义为具有2个或更少受累血管区域的对象。
CV风险因素与亚临床动脉粥样硬化的评估。在PESA研究中,通过如前所述的问卷调查(吸烟、家族史)或客观定量(高血压、糖尿病、血脂异常)来前瞻性地收集CV风险因素(Fernandez-Friera L等人,2015)。在所有参与者中进行如前所述的二维血管超声和非增强心脏计算机断层摄影(Fernandez-Friera L等人,2015;Fernandez-Friera L等人,2017)。通过颈动脉、肾下腹主动脉和髂股动脉的横断面扫描来评估通过超声的动脉粥样硬化斑块的存在。颈动脉和股动脉中的斑块的鉴定以及AWHS研究中的临床特点如所述测定(Laclaustra M等人,2016)。
组织样品。来自中间层和内膜层的主动脉组织样品获自法国生物医学机构授权的死亡器官供体(PFS 09-007,BRIF BB-0033-00029;AoS BBMRI-EU/infrastructureBIOBANQUE;No.Access:2,Last:April 15,2014.[BIORESOURCE]))。这些样品中的一些在宏观上是正常的(AoS)并且没有早期动脉粥样化病变,并且被用作健康对照(9个个体)用于与具有脂肪条纹(FS)(对于中间层为7个个体,并且在内膜层的情况下,为6个个体)或纤维脂质(FL)斑块(在中间层的情况下为11个个体,并且在内膜层的情况下,为12个个体)的样品进行比较。将组织(100mg的FL、FS或AoS)在低温下匀浆,并将裂解物重悬于缓冲液(50mM碘乙酰胺(Sigma),1%SDS,1mM EDTA,100mM Tris-HCL,pH8.5)中用于蛋白质提取或者重悬于TRIZOL中用于mRNA分离。通过在冰上以15分钟的间隔将样品涡旋4次来提取蛋白质。通过BCA方法测量上清液中的蛋白质并将其储存在-80℃直到蛋白质组学分析。
蛋白质组学分析。根据制造商的说明(Nanosep Centrifugal Devices withOmega Membrane-10K,PALL),用胰蛋白酶对血浆和组织蛋白样品进行过滤辅助消化,并用TMT试剂(Thermo Fisher Scintific)对所得肽进行多重同重元素标记。(Baldan-Martin M等人,2018;Bagwan N等人,2018)。将10个通道中的两个保留用于通过合并样品产生的内部参考标准样品。使用高pH反相肽分级分离试剂盒(Thermo Fisher Scientific)将血浆肽分成5种级分,并且使用OASIS MCX柱将组织肽分成8种级分。使用通过纳米电喷雾离子源(Thermo Fisher Scientific,Bremen,Germany)与Q Exactive HF质谱仪(Thermo FisherScientific,Bremen,Germany)偶联的Ultimate 3000HPLC系统(Thermo FisherScientific),通过LC-MS/MS分析每种血浆级分(Bagwan N等人,2018)。在与OrbitrapFusion质谱仪(Themo Scientific)偶联的Easy nLC 1000液相色谱系统上分析组织级分。(Baldan-Martin M等人,2018)
免疫比浊分析。使用Binding Site Optilite分析器通过免疫比浊测定(分别为LK088.OPT、NK058.OPT和LK098.OPT)测量IGHA2、HPT和APOA的血浆水平。分析由来自TheBinding Site公司的技术人员以盲目的方式进行。
统计分析。使用我们实验室中开发的模型进行肽鉴定、定量以及统计和系统生物学分析(Navarro P等人,2014;Navarro P and Vazquez J,2008;Jorge I等人,2009;Garcia-Marques F等人,2016;Bonzon-Kulichenko E等人,2016;Martinez-Bartolome S等人,2008)。从TMT标记的肽的MS/MS光谱提取定量信息。使用WSPP模型分析肽定量,所述WSPP模型使用原始定量作为输入数据,并计算每个个体相对于两个参考内标样品的平均值的蛋白质log2倍数变化。在该模型中,蛋白质log2-比率表示为根据它们的估计方差(Zq值)以标准偏差为单位的标准变量。
使用SPSS软件(IBM,Armonk,New York),使用调整的线性和逻辑回归模型分析蛋白质与动脉粥样硬化的存在和程度的关联。进行多变量分析以探索与临床关联的候选变量:葡萄糖、LDL,HDL、收缩压和舒张压、吸烟和年龄。关联表示为具有95%置信区间(CI)的比值比(OR)。在p值<0.05时,差异被认为是显著的,被认为是统计学显著的。计算每个模型的接受者操作特点(ROC)曲线下的C统计量或面积(AUC),作为每个生物标志物蛋白质组的判别能力。根据DeLong(DeLong ER等人,1988)的方法进行包括或不包括由生物标志物组提供的信息的模型的C-指数的比较。为了评价生物标志物组是否有助于根据亚临床动脉粥样硬化的存在和程度对个体进行正确地分类,我们使用四个离散风险类别(NRI0.25)和无类别的净重新分类指数(NRI>0)(也称为连续的净重新分类指数来计算分类净重新分类指数(Kerr KF等人,2014,Pepe MS等人,2015;Leening MJ等人,2014),其不依赖于对类别的任意选择,而是认为适当时在正确的方向上预测风险的任何变化。在低风险亚群中,我们评价了生物标志物组是否有助于使用两个风险类别(风险/无风险)(NRI0.5)根据亚临床动脉粥样硬化的存在对个体进行分类。
研究设计
目前的报告检查了PESA研究的子队列(Fernandez-Ortiz A等人,2013)。用于发现阶段的第一队列(PESA-V1)包括平均年龄为48.5岁的444名男性,被组织成222对没有动脉粥样硬化临床史的个体。PESA-V1队列的完全临床特点在表13中详述。来自PESA-V1的血浆样品通过深度定量蛋白质组学进行分析。
表13-用于发现阶段的PESA-V1群体的特征
检测到的蛋白质丰度变化随时间的稳定性通过在三年后用从相同个体(PESA-V2)收集的血浆重复蛋白质组学分析来确认(除了没有更新对“组学”分析的同意的四个个体之外);PESA-V2个体的临床特点描述于补充表1中。蛋白质组学定量每个个体的平均1093种蛋白质,并且可以在超过80%的个体中定量454种蛋白质。884个血浆样品的分析需要总共560次LC-MS运行。
表14-PESA-V2群体的特征
数值为平均值±SD或%
对于验证阶段,我们检查了来自亚拉贡工作者健康研究(Aragon Workers HealthStudy,AWHS)的350名男性的第三队列。该队列的平均年龄为50.3岁,被组织成没有临床CV疾病史并且具有与PESA亚队列相似的临床特点的175对个体(表15)。(Casasnovas JA等人,2012;Laclaustra M等人,2016)。来自AWHS队列的血浆样品使用商购可获得的针对所选蛋白的抗体通过比浊法进行分析。
表15-用于验证阶段的AWHS群体的特征
数值为平均值±SD或%
2.1血浆蛋白与传统风险因素的关联
构建了相关网络,其包括在PESA-V1和PESA-V2样品集中水平与传统的连续CV风险因素显著相关的蛋白质;所考虑的CV风险因素为葡萄糖、年龄、收缩压和舒张压、胆固醇、LDL和HDL(图2)。大多数相关性是载脂蛋白和其它参与脂质转运的蛋白质,其显示与LDL、HDL和胆固醇正相关。除了这些预期的关联之外,与其它因素没有清楚的关联模式,表明在亚临床阶段,传统CV风险因素对血浆蛋白质组具有有限的影响。
2.2血浆蛋白与斑块厚度和钙评分的关联
血浆蛋白水平与斑块厚度之间的关联通过经多重假设检验校正的单变量线性回归分析来评估。该分析显示了在PESA-V1中显示出与斑块厚度显著相关(FDR<5%)的血浆蛋白列表(表16)。大多数蛋白质在3年随访时保持与斑块厚度的相关性(PESA-V2),其中FDR低于15%(表16)。这些蛋白质大部分与体液免疫应答有关,包括增加的聚合免疫球蛋白受体(PIGR)和IGHA2,以及降低的免疫球蛋白重链恒定γ2(immunoglobulin heavy constantgamma 2,IGHG2)、免疫球蛋白κ恒定区(immunoglobulin kappa constant,IGKC)、免疫球蛋白重链恒定γ1(immunoglobulin heavy constant gamma 1,IGHG1)和免疫球蛋白λ恒定2(immunoglobulin lambda constant 2,IGLC2)。三年之后,HPT、C4结合蛋白(C4BP)、肝素辅因子2(HEP2)、APOA、补体成分9(CO9)和凝溶胶蛋白(GELS)也保持它们与斑块厚度的相关性(表16)。我们还注意到在PESA-V1中,血管粘附蛋白1(VCAM1)和血管性血友病因子(VWF)(被认为是内皮功能障碍的生物标志物的两种蛋白质)的水平随着斑块厚度而降低(表16)。尽管这种趋势与预期的相反,但这种观察在PESA-V2中没有再现。
表16-显示与斑块厚度显著相关的蛋白质。进行线性回归分析以测量PESA-V1和PESA-V2中斑块厚度与血浆蛋白水平之间的相关性。皮尔逊相关系数的统计显著性以错误发现率(FDR)表示。列出了在V1(FDR≤5%)和V2(FDR≤15%)中具有显著相关性的蛋白质。
通常,PESA-V1中与斑块厚度的相关性在PESA-V2中再现(图3A)。有趣的是,在V1中观察到的相关性中,与体液免疫应答相关的蛋白质在V2中更好保持的那些蛋白质中(图3A)。与IGLC2、IGKC、IGHG1和IGHG2相比,IGHA2和免疫球蛋白重链恒定区δ(immunoglobulinheavy constant delta,IGHD)与斑块厚度相反关联,以及相关同种型免疫球蛋白重链恒定区α1(IGHA1)和免疫球蛋白重链恒定区γ3和4(分别为IGHG3和IGHG34)缺乏关联,表明斑块形成与同种型转换有关。
在与斑块厚度相关的蛋白质中,我们判断IGHA2、PIGR、HEP2、HPT、APOA、GELS、IGKC、IGLC2和IGHG1是在通过使用多元线性回归分析调整个体风险因素之后在PESA-V1和V2中更好地保持相关性的蛋白质(表17)。
表17-血浆蛋白水平与斑块厚度的相关性。进行二元线性回归分析以测量与通过已知风险因素中的每一种调整之后PESA-V1和PESA-V2队列中的斑块厚度与所指示的血浆蛋白水平之间的相关性。皮尔逊相关系数的统计学显著性以p值表示。
由于这些结果是在通过蛋白质组学分析大量蛋白质之后获得的,我们研究了它们中的一些是否可以使用其它方法再现。商购可获得的抗体所针对的两种代表性蛋白质(IGHA2和APOA)的血浆水平的比浊法分析确认了它们与斑块厚度的独立相关性(表18)。
表18-通过基于抗体的方法验证一些蛋白质组学结果。通过比浊法测量IGHA2和APOA的血浆水平。进行二元线性回归分析以测量在通过已知风险因素中的每一种调整之后PESA-V1队列中的斑块厚度与蛋白质水平之间的相关性。皮尔逊相关系数的统计显著性以p值表示。
用与冠状动脉钙评分(CACS)相关的蛋白质进行相似的分析。在PESA-V1中,一些与斑块厚度相关的蛋白质,包括HPT、APOA和GELS,也显示与CACS显著相关,这保持在V2中(表19和图3B)。
表19-显示与冠状动脉钙评分显著相关的蛋白质。进行线性回归分析以测量PESA-V1和PESA-V2中CACS与血浆蛋白水平之间的相关性。皮尔逊相关系数的统计显著性以错误发现率(FDR)表示。列出了在V1(FDR≤5%)和V2(FDR≤15%)中具有显著相关性的蛋白质。
然而,在与体液免疫应答相关的蛋白质中,仅IGKC保持其与CACS的相关性(表19和图3B)。补体因子B(CFB)、免疫球蛋白重常数μ(IGHM)和CD5抗原样(CD5L)是与CACS相关但与斑块厚度无关的其它蛋白质。在与CACS相关的蛋白质中,HPT、APOA、GELS、CD5L和IGKC是在通过风险因素调整之后在PESA-V1和V2中更好地维持相关性的蛋白质(表20)。
表20-血浆蛋白水平与钙评分的相关性。进行二元线性回归分析以测量通过已知风险因素中的每一种调整之后PESA-V1和PESA-V2队列中CACS与指定的血浆蛋白水平之间的相关性。皮尔逊相关系数的统计显著性以p值表示。
我们还分析了代表性急性期蛋白(包括C-反应蛋白(CRP)、血清淀粉样蛋白A-1(SAA1)和α-1-酸性糖蛋白1(ORM1))和先前描述的与亚临床动脉粥样硬化相关的其它蛋白的行为(表21)。虽然在PESA-V2中CRP与斑块厚度相关,但在两次PESA访问中没有一种急性期蛋白保持稳定的相关性。在先前提出的与亚临床动脉粥样硬化相关的蛋白质中(Saarikoski LA等人,2010;Bhosale SD等人,2018),钙粘蛋白-13(CDH13)在PESA-V1中显示与斑块厚度显著相关,但在PESA-V2中未确认结果。在两次访问的任何一次中都没有检测到与CACS的关联。
表21-代表性急性期蛋白和与描述为与亚临床动脉粥样硬化相关的蛋白的斑块厚度与钙评分的相关性
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2.3血浆蛋白改变与亚临床动脉粥样硬化之间的关联独立于风险评分
进行逻辑回归分析以确定血浆蛋白水平对参与者患有亚临床动脉粥样硬化疾病的可能性的影响。PIGR、IGHA2、APOA、HPT和HEP2的血浆水平增加与疾病可能性的增加显著相关,并且在通过FHS 10年评分调整之后,关联仍然显著(表22和图4)。IGHG1水平的降低也与FHS 10年评分调整之后的疾病相关(表22)。CD5L并不显著相关,并且GELS和IGKC在通过FHS 10年评分调整之后失去了它们与亚临床动脉粥样硬化的关联(表22)。
表22-与亚临床动脉粥样硬化的存在相关的逻辑回归分析。比值比是指使用单变量逻辑回归模型(单变量)或通过FHS 10年评分调整(Adj.F10Y)的双变量模型,通过蛋白质组学测定的并且以标准偏差为单位表示的相对蛋白质值。
为了选择生物标志物组,使用多变量逻辑回归模型测试几种蛋白质组合。当在同一组中包括其它蛋白质时,IGHG1没有达到统计学显著性,而PIGR、IGHA2、APOA、HPT和HEP2可以组合以形成若干三蛋白质组,其中PIGR可以被IGHA2替代以及HEP2可以被HPT替代(表23)。通过BEWAT或ICHS风险评分调整之后,这五种蛋白与亚临床动脉粥样硬化的个体关联仍然显著(图4)。
表23-用于预测PESA-V1中亚临床动脉粥样硬化的多变量逻辑回归模型。使用多变量逻辑回归模型来确定蛋白值与亚临床动脉粥样硬化存在的关联。
2.4与亚临床动脉粥样硬化相关的血浆蛋白在早期动脉粥样硬化病变中累积
我们测定了早期人类动脉粥样硬化病变(脂肪条纹和纤维脂质斑块)的中间层和内膜层中五种所选蛋白质的丰度。定量蛋白质组学分析显示了相对于中间层,内膜层中PIGR、IGHA2、APOA、HPT和HEP2的绝对丰度显著升高(图5)。随着病变从脂肪条纹进展到纤维脂质阶段,这五种蛋白质的内膜累积进一步增加(图5)。因此,与血浆中亚临床动脉粥样硬化有关的五种蛋白质也在斑块形成的初始阶段在动脉粥样硬化病变中累积。
2.5在来自亚拉贡工作者健康研究(AWHS)的队列中的验证。
对于验证阶段,我们选择了由IGHA2、APOA和HPT组成的组,因为这些蛋白质可以使用临床上使用的可商购获得的基于抗体的试剂盒测量。用从AWHS队列获得的一组350个血浆样品进行验证研究。多变量逻辑回归分析显示了三种蛋白质中每一种的血浆浓度增加与亚临床动脉粥样硬化可能性的增加显著相关(图6A)。这种趋势在通过三个风险评分中的任一个调整之后保持,表明这些蛋白质的水平独立地与AWHS群体中的亚临床动脉粥样硬化相关(图6B-D)。
2.6蛋白质生物标志物组的预测值
包括作为生物标志物组的三种蛋白质通过单独的风险评分改善亚临床动脉粥样硬化预测的能力通过接受者操作特点(ROC)分析来评估。在PESA-V1队列中,由三种蛋白质和FHS 10年评分组成的组比单独的FHS 10年评分(0.71:0.66-0.77,p<0.05,DeLong检验)(图7A)产生显著更好的AUC(0.76:0.71-0.81 95%CI)。由蛋白质组产生的分类和连续NRI分别是NRI0.25=7%和NRI>0=40%(表24)。蛋白质组还改善了AWHS队列中的疾病预测(AUC=0.72:0.66-0.77对比0.61:0.54-0.69,p<0.01)(图7A),产生了NRI0.25=29%和NRI>0=51%。生物标志物组还显著改善BEWAT评分(图7B)和ICHS评分(图7C)的AUC,其中在两个群体中,NRI高于16%并且在一些情况下达到64%(表24)。通过仅两种蛋白质的一些组合,例如IGHA2和HPT或APOA和HPT,也显著改善了AUC(图7和表24)。
表24-蛋白质生物标志物组的净重新分类指数。列出了分类(NRI0.25)和连续(NRI>0)的净重新分类指数以评价相对于通过单独的风险评分(FHS 10年,BEWAT或ICHS)所实现的,根据亚临床动脉粥样硬化的存在和程度对个体进行正确地分类的性能的改善。为了计算NRI0.25,将个体分为四个离散风险类别。
为了根据风险评分评估这些蛋白质是否提供关于处于CV事件低风险的个体的有用信息,我们选择了FHS 10年评分<0.1的参与者亚群(Fernandez-Friera L等人,2015;Pencina MJ等人,2009;Ford ES等人,2004)。在这个亚群中,3种蛋白质生物标志物组有效地预测PESA-V1中的亚临床疾病(AUC=0.62:0.56-0.68,p<0.001对比AUC=0.5)(图8,左边),产生了5-8%的NRI(表25)。3种蛋白质组还预测AWHS亚群中的疾病(AUC=0.68:0.6-0.76,p<0.0001对比AUC=0.5)(图8,右边),其中NRI范围为10-36%(表25)。通过仅2种蛋白质的一些组合有效地预测两个群体中的亚临床动脉粥样硬化(图8)。
表25-低风险群体中蛋白质生物标志物组的净重新分类指数。列出了分类的(NRI0.5)净重新分类指数以根据低风险亚群中亚临床动脉粥样硬化在的存在和程度来评价对个体进行正确分类的性能改善(FHS 10年评分<0.1)。将两个离散类别(风险/无风险)用于计算NRI0.5。
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吉米内兹·迪亚兹基础卫生研究基金会;
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Asp Ser Asn Ser Asn Lys Lys Asn Ala Asp Leu Gln Val Leu Lys Pro
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Glu Pro Glu Leu Val Tyr Glu Asp Leu Arg Gly Ser Val Thr Phe His
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Cys Ala Leu Gly Pro Glu Val Ala Asn Val Ala Lys Phe Leu Cys Arg
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Gln Ser Ser Gly Glu Asn Cys Asp Val Val Val Asn Thr Leu Gly Lys
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Arg Ala Pro Ala Phe Glu Gly Arg Ile Leu Leu Asn Pro Gln Asp Lys
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Asp Gly Ser Phe Ser Val Val Ile Thr Gly Leu Arg Lys Glu Asp Ala
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Gly Arg Tyr Leu Cys Gly Ala His Ser Asp Gly Gln Leu Gln Glu Gly
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Ser Pro Ile Gln Ala Trp Gln Leu Phe Val Asn Glu Glu Ser Thr Ile
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Pro Arg Ser Pro Thr Val Val Lys Gly Val Ala Gly Gly Ser Val Ala
355 360 365
Val Leu Cys Pro Tyr Asn Arg Lys Glu Ser Lys Ser Ile Lys Tyr Trp
370 375 380
Cys Leu Trp Glu Gly Ala Gln Asn Gly Arg Cys Pro Leu Leu Val Asp
385 390 395 400
Ser Glu Gly Trp Val Lys Ala Gln Tyr Glu Gly Arg Leu Ser Leu Leu
405 410 415
Glu Glu Pro Gly Asn Gly Thr Phe Thr Val Ile Leu Asn Gln Leu Thr
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Ser Arg Asp Ala Gly Phe Tyr Trp Cys Leu Thr Asn Gly Asp Thr Leu
435 440 445
Trp Arg Thr Thr Val Glu Ile Lys Ile Ile Glu Gly Glu Pro Asn Leu
450 455 460
Lys Val Pro Gly Asn Val Thr Ala Val Leu Gly Glu Thr Leu Lys Val
465 470 475 480
Pro Cys His Phe Pro Cys Lys Phe Ser Ser Tyr Glu Lys Tyr Trp Cys
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Lys Trp Asn Asn Thr Gly Cys Gln Ala Leu Pro Ser Gln Asp Glu Gly
500 505 510
Pro Ser Lys Ala Phe Val Asn Cys Asp Glu Asn Ser Arg Leu Val Ser
515 520 525
Leu Thr Leu Asn Leu Val Thr Arg Ala Asp Glu Gly Trp Tyr Trp Cys
530 535 540
Gly Val Lys Gln Gly His Phe Tyr Gly Glu Thr Ala Ala Val Tyr Val
545 550 555 560
Ala Val Glu Glu Arg Lys Ala Ala Gly Ser Arg Asp Val Ser Leu Ala
565 570 575
Lys Ala Asp Ala Ala Pro Asp Glu Lys Val Leu Asp Ser Gly Phe Arg
580 585 590
Glu Ile Glu Asn Lys Ala Ile Gln Asp Pro Arg Leu Phe Ala Glu Glu
595 600 605
Lys Ala Val Ala Asp Thr Arg Asp Gln Ala Asp Gly Ser Arg Ala Ser
610 615 620
Val Asp Ser Gly Ser Ser Glu Glu Gln Gly Gly Ser Ser Arg Ala Leu
625 630 635 640
Val Ser Thr Leu Val Pro Leu Gly Leu Val Leu Ala Val Gly Ala Val
645 650 655
Ala Val Gly Val Ala Arg Ala Arg His Arg Lys Asn Val Asp Arg Val
660 665 670
Ser Ile Arg Ser Tyr Arg Thr Asp Ile Ser Met Ser Asp Phe Glu Asn
675 680 685
Ser Arg Glu Phe Gly Ala Asn Asp Asn Met Gly Ala Ser Ser Ile Thr
690 695 700
Gln Glu Thr Ser Leu Gly Gly Lys Glu Glu Phe Val Ala Thr Thr Glu
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Ser Thr Thr Glu Thr Lys Glu Pro Lys Lys Ala Lys Arg Ser Ser Lys
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Val Ala Ala Glu Ala Gln Asp Gly Pro Gln Glu Ala
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Ala Ser Pro Thr Ser Pro Lys Val Phe Pro Leu Ser Leu Asp Ser Thr
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Pro Gln Asp Gly Asn Val Val Val Ala Cys Leu Val Gln Gly Phe Phe
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Pro Gln Glu Pro Leu Ser Val Thr Trp Ser Glu Ser Gly Gln Asn Val
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Thr Ala Arg Asn Phe Pro Pro Ser Gln Asp Ala Ser Gly Asp Leu Tyr
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Thr Thr Ser Ser Gln Leu Thr Leu Pro Ala Thr Gln Cys Pro Asp Gly
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Arg Leu Ser Leu His Arg Pro Ala Leu Glu Asp Leu Leu Leu Gly Ser
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Pro Pro Glu Arg Asp Leu Cys Gly Cys Tyr Ser Val Ser Ser Val Leu
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Ala Ala His Pro Glu Leu Lys Thr Pro Leu Thr Ala Asn Ile Thr Lys
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Ser Gly Asn Thr Phe Arg Pro Glu Val His Leu Leu Pro Pro Pro Ser
210 215 220
Glu Glu Leu Ala Leu Asn Glu Leu Val Thr Leu Thr Cys Leu Ala Arg
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Gly Phe Ser Pro Lys Asp Val Leu Val Arg Trp Leu Gln Gly Ser Gln
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Glu Leu Pro Arg Glu Lys Tyr Leu Thr Trp Ala Ser Arg Gln Glu Pro
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Ser Gln Gly Thr Thr Thr Tyr Ala Val Thr Ser Ile Leu Arg Val Ala
275 280 285
Ala Glu Asp Trp Lys Lys Gly Glu Thr Phe Ser Cys Met Val Gly His
290 295 300
Glu Ala Leu Pro Leu Ala Phe Thr Gln Lys Thr Ile Asp Arg Met Ala
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Gly Lys Pro Thr His Ile Asn Val Ser Val Val Met Ala Glu Ala Asp
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Gly Thr Cys Tyr
340
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Met Glu His Lys Glu Val Val Leu Leu Leu Leu Leu Phe Leu Lys Ser
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Ala Ala Pro Glu Gln Ser His Val Val Gln Asp Cys Tyr His Gly Asp
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Gly Gln Ser Tyr Arg Gly Thr Tyr Ser Thr Thr Val Thr Gly Arg Thr
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Cys Gln Ala Trp Ser Ser Met Thr Pro His Gln His Asn Arg Thr Thr
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Glu Asn Tyr Pro Asn Ala Gly Leu Ile Met Asn Tyr Cys Arg Asn Pro
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Asp Ala Val Ala Ala Pro Tyr Cys Tyr Thr Arg Asp Pro Gly Val Arg
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Trp Glu Tyr Cys Asn Leu Thr Gln Cys Ser Asp Ala Glu Gly Thr Ala
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Val Ala Pro Pro Thr Val Thr Pro Val Pro Ser Leu Glu Ala Pro Ser
115 120 125
Glu Gln Ala Pro Thr Glu Gln Arg Pro Gly Val Gln Glu Cys Tyr His
130 135 140
Gly Asn Gly Gln Ser Tyr Arg Gly Thr Tyr Ser Thr Thr Val Thr Gly
145 150 155 160
Arg Thr Cys Gln Ala Trp Ser Ser Met Thr Pro His Ser His Ser Arg
165 170 175
Thr Pro Glu Tyr Tyr Pro Asn Ala Gly Leu Ile Met Asn Tyr Cys Arg
180 185 190
Asn Pro Asp Ala Val Ala Ala Pro Tyr Cys Tyr Thr Arg Asp Pro Gly
195 200 205
Val Arg Trp Glu Tyr Cys Asn Leu Thr Gln Cys Ser Asp Ala Glu Gly
210 215 220
Thr Ala Val Ala Pro Pro Thr Val Thr Pro Val Pro Ser Leu Glu Ala
225 230 235 240
Pro Ser Glu Gln Ala Pro Thr Glu Gln Arg Pro Gly Val Gln Glu Cys
245 250 255
Tyr His Gly Asn Gly Gln Ser Tyr Arg Gly Thr Tyr Ser Thr Thr Val
260 265 270
Thr Gly Arg Thr Cys Gln Ala Trp Ser Ser Met Thr Pro His Ser His
275 280 285
Ser Arg Thr Pro Glu Tyr Tyr Pro Asn Ala Gly Leu Ile Met Asn Tyr
290 295 300
Cys Arg Asn Pro Asp Ala Val Ala Ala Pro Tyr Cys Tyr Thr Arg Asp
305 310 315 320
Pro Gly Val Arg Trp Glu Tyr Cys Asn Leu Thr Gln Cys Ser Asp Ala
325 330 335
Glu Gly Thr Ala Val Ala Pro Pro Thr Val Thr Pro Val Pro Ser Leu
340 345 350
Glu Ala Pro Ser Glu Gln Ala Pro Thr Glu Gln Arg Pro Gly Val Gln
355 360 365
Glu Cys Tyr His Gly Asn Gly Gln Ser Tyr Arg Gly Thr Tyr Ser Thr
370 375 380
Thr Val Thr Gly Arg Thr Cys Gln Ala Trp Ser Ser Met Thr Pro His
385 390 395 400
Ser His Ser Arg Thr Pro Glu Tyr Tyr Pro Asn Ala Gly Leu Ile Met
405 410 415
Asn Tyr Cys Arg Asn Pro Asp Ala Val Ala Ala Pro Tyr Cys Tyr Thr
420 425 430
Arg Asp Pro Gly Val Arg Trp Glu Tyr Cys Asn Leu Thr Gln Cys Ser
435 440 445
Asp Ala Glu Gly Thr Ala Val Ala Pro Pro Thr Val Thr Pro Val Pro
450 455 460
Ser Leu Glu Ala Pro Ser Glu Gln Ala Pro Thr Glu Gln Arg Pro Gly
465 470 475 480
Val Gln Glu Cys Tyr His Gly Asn Gly Gln Ser Tyr Arg Gly Thr Tyr
485 490 495
Ser Thr Thr Val Thr Gly Arg Thr Cys Gln Ala Trp Ser Ser Met Thr
500 505 510
Pro His Ser His Ser Arg Thr Pro Glu Tyr Tyr Pro Asn Ala Gly Leu
515 520 525
Ile Met Asn Tyr Cys Arg Asn Pro Asp Ala Val Ala Ala Pro Tyr Cys
530 535 540
Tyr Thr Arg Asp Pro Gly Val Arg Trp Glu Tyr Cys Asn Leu Thr Gln
545 550 555 560
Cys Ser Asp Ala Glu Gly Thr Ala Val Ala Pro Pro Thr Val Thr Pro
565 570 575
Val Pro Ser Leu Glu Ala Pro Ser Glu Gln Ala Pro Thr Glu Gln Arg
580 585 590
Pro Gly Val Gln Glu Cys Tyr His Gly Asn Gly Gln Ser Tyr Arg Gly
595 600 605
Thr Tyr Ser Thr Thr Val Thr Gly Arg Thr Cys Gln Ala Trp Ser Ser
610 615 620
Met Thr Pro His Ser His Ser Arg Thr Pro Glu Tyr Tyr Pro Asn Ala
625 630 635 640
Gly Leu Ile Met Asn Tyr Cys Arg Asn Pro Asp Ala Val Ala Ala Pro
645 650 655
Tyr Cys Tyr Thr Arg Asp Pro Gly Val Arg Trp Glu Tyr Cys Asn Leu
660 665 670
Thr Gln Cys Ser Asp Ala Glu Gly Thr Ala Val Ala Pro Pro Thr Val
675 680 685
Thr Pro Val Pro Ser Leu Glu Ala Pro Ser Glu Gln Ala Pro Thr Glu
690 695 700
Gln Arg Pro Gly Val Gln Glu Cys Tyr His Gly Asn Gly Gln Ser Tyr
705 710 715 720
Arg Gly Thr Tyr Ser Thr Thr Val Thr Gly Arg Thr Cys Gln Ala Trp
725 730 735
Ser Ser Met Thr Pro His Ser His Ser Arg Thr Pro Glu Tyr Tyr Pro
740 745 750
Asn Ala Gly Leu Ile Met Asn Tyr Cys Arg Asn Pro Asp Ala Val Ala
755 760 765
Ala Pro Tyr Cys Tyr Thr Arg Asp Pro Gly Val Arg Trp Glu Tyr Cys
770 775 780
Asn Leu Thr Gln Cys Ser Asp Ala Glu Gly Thr Ala Val Ala Pro Pro
785 790 795 800
Thr Val Thr Pro Val Pro Ser Leu Glu Ala Pro Ser Glu Gln Ala Pro
805 810 815
Thr Glu Gln Arg Pro Gly Val Gln Glu Cys Tyr His Gly Asn Gly Gln
820 825 830
Ser Tyr Arg Gly Thr Tyr Ser Thr Thr Val Thr Gly Arg Thr Cys Gln
835 840 845
Ala Trp Ser Ser Met Thr Pro His Ser His Ser Arg Thr Pro Glu Tyr
850 855 860
Tyr Pro Asn Ala Gly Leu Ile Met Asn Tyr Cys Arg Asn Pro Asp Ala
865 870 875 880
Val Ala Ala Pro Tyr Cys Tyr Thr Arg Asp Pro Gly Val Arg Trp Glu
885 890 895
Tyr Cys Asn Leu Thr Gln Cys Ser Asp Ala Glu Gly Thr Ala Val Ala
900 905 910
Pro Pro Thr Val Thr Pro Val Pro Ser Leu Glu Ala Pro Ser Glu Gln
915 920 925
Ala Pro Thr Glu Gln Arg Pro Gly Val Gln Glu Cys Tyr His Gly Asn
930 935 940
Gly Gln Ser Tyr Arg Gly Thr Tyr Ser Thr Thr Val Thr Gly Arg Thr
945 950 955 960
Cys Gln Ala Trp Ser Ser Met Thr Pro His Ser His Ser Arg Thr Pro
965 970 975
Glu Tyr Tyr Pro Asn Ala Gly Leu Ile Met Asn Tyr Cys Arg Asn Pro
980 985 990
Asp Ala Val Ala Ala Pro Tyr Cys Tyr Thr Arg Asp Pro Gly Val Arg
995 1000 1005
Trp Glu Tyr Cys Asn Leu Thr Gln Cys Ser Asp Ala Glu Gly Thr
1010 1015 1020
Ala Val Ala Pro Pro Thr Val Thr Pro Val Pro Ser Leu Glu Ala
1025 1030 1035
Pro Ser Glu Gln Ala Pro Thr Glu Gln Arg Pro Gly Val Gln Glu
1040 1045 1050
Cys Tyr His Gly Asn Gly Gln Ser Tyr Arg Gly Thr Tyr Ser Thr
1055 1060 1065
Thr Val Thr Gly Arg Thr Cys Gln Ala Trp Ser Ser Met Thr Pro
1070 1075 1080
His Ser His Ser Arg Thr Pro Glu Tyr Tyr Pro Asn Ala Gly Leu
1085 1090 1095
Ile Met Asn Tyr Cys Arg Asn Pro Asp Ala Val Ala Ala Pro Tyr
1100 1105 1110
Cys Tyr Thr Arg Asp Pro Gly Val Arg Trp Glu Tyr Cys Asn Leu
1115 1120 1125
Thr Gln Cys Ser Asp Ala Glu Gly Thr Ala Val Ala Pro Pro Thr
1130 1135 1140
Val Thr Pro Val Pro Ser Leu Glu Ala Pro Ser Glu Gln Ala Pro
1145 1150 1155
Thr Glu Gln Arg Pro Gly Val Gln Glu Cys Tyr His Gly Asn Gly
1160 1165 1170
Gln Ser Tyr Arg Gly Thr Tyr Ser Thr Thr Val Thr Gly Arg Thr
1175 1180 1185
Cys Gln Ala Trp Ser Ser Met Thr Pro His Ser His Ser Arg Thr
1190 1195 1200
Pro Glu Tyr Tyr Pro Asn Ala Gly Leu Ile Met Asn Tyr Cys Arg
1205 1210 1215
Asn Pro Asp Ala Val Ala Ala Pro Tyr Cys Tyr Thr Arg Asp Pro
1220 1225 1230
Gly Val Arg Trp Glu Tyr Cys Asn Leu Thr Gln Cys Ser Asp Ala
1235 1240 1245
Glu Gly Thr Ala Val Ala Pro Pro Thr Val Thr Pro Val Pro Ser
1250 1255 1260
Leu Glu Ala Pro Ser Glu Gln Ala Pro Thr Glu Gln Arg Pro Gly
1265 1270 1275
Val Gln Glu Cys Tyr His Gly Asn Gly Gln Ser Tyr Arg Gly Thr
1280 1285 1290
Tyr Ser Thr Thr Val Thr Gly Arg Thr Cys Gln Ala Trp Ser Ser
1295 1300 1305
Met Thr Pro His Ser His Ser Arg Thr Pro Glu Tyr Tyr Pro Asn
1310 1315 1320
Ala Gly Leu Ile Met Asn Tyr Cys Arg Asn Pro Asp Ala Val Ala
1325 1330 1335
Ala Pro Tyr Cys Tyr Thr Arg Asp Pro Gly Val Arg Trp Glu Tyr
1340 1345 1350
Cys Asn Leu Thr Gln Cys Ser Asp Ala Glu Gly Thr Ala Val Ala
1355 1360 1365
Pro Pro Thr Val Thr Pro Val Pro Ser Leu Glu Ala Pro Ser Glu
1370 1375 1380
Gln Ala Pro Thr Glu Gln Arg Pro Gly Val Gln Glu Cys Tyr His
1385 1390 1395
Gly Asn Gly Gln Ser Tyr Arg Gly Thr Tyr Ser Thr Thr Val Thr
1400 1405 1410
Gly Arg Thr Cys Gln Ala Trp Ser Ser Met Thr Pro His Ser His
1415 1420 1425
Ser Arg Thr Pro Glu Tyr Tyr Pro Asn Ala Gly Leu Ile Met Asn
1430 1435 1440
Tyr Cys Arg Asn Pro Asp Ala Val Ala Ala Pro Tyr Cys Tyr Thr
1445 1450 1455
Arg Asp Pro Gly Val Arg Trp Glu Tyr Cys Asn Leu Thr Gln Cys
1460 1465 1470
Ser Asp Ala Glu Gly Thr Ala Val Ala Pro Pro Thr Val Thr Pro
1475 1480 1485
Val Pro Ser Leu Glu Ala Pro Ser Glu Gln Ala Pro Thr Glu Gln
1490 1495 1500
Arg Pro Gly Val Gln Glu Cys Tyr His Gly Asn Gly Gln Ser Tyr
1505 1510 1515
Arg Gly Thr Tyr Ser Thr Thr Val Thr Gly Arg Thr Cys Gln Ala
1520 1525 1530
Trp Ser Ser Met Thr Pro His Ser His Ser Arg Thr Pro Glu Tyr
1535 1540 1545
Tyr Pro Asn Ala Gly Leu Ile Met Asn Tyr Cys Arg Asn Pro Asp
1550 1555 1560
Ala Val Ala Ala Pro Tyr Cys Tyr Thr Arg Asp Pro Gly Val Arg
1565 1570 1575
Trp Glu Tyr Cys Asn Leu Thr Gln Cys Ser Asp Ala Glu Gly Thr
1580 1585 1590
Ala Val Ala Pro Pro Thr Val Thr Pro Val Pro Ser Leu Glu Ala
1595 1600 1605
Pro Ser Glu Gln Ala Pro Thr Glu Gln Arg Pro Gly Val Gln Glu
1610 1615 1620
Cys Tyr His Gly Asn Gly Gln Ser Tyr Arg Gly Thr Tyr Ser Thr
1625 1630 1635
Thr Val Thr Gly Arg Thr Cys Gln Ala Trp Ser Ser Met Thr Pro
1640 1645 1650
His Ser His Ser Arg Thr Pro Glu Tyr Tyr Pro Asn Ala Gly Leu
1655 1660 1665
Ile Met Asn Tyr Cys Arg Asn Pro Asp Ala Val Ala Ala Pro Tyr
1670 1675 1680
Cys Tyr Thr Arg Asp Pro Gly Val Arg Trp Glu Tyr Cys Asn Leu
1685 1690 1695
Thr Gln Cys Ser Asp Ala Glu Gly Thr Ala Val Ala Pro Pro Thr
1700 1705 1710
Val Thr Pro Val Pro Ser Leu Glu Ala Pro Ser Glu Gln Ala Pro
1715 1720 1725
Thr Glu Gln Arg Pro Gly Val Gln Glu Cys Tyr His Gly Asn Gly
1730 1735 1740
Gln Ser Tyr Arg Gly Thr Tyr Ser Thr Thr Val Thr Gly Arg Thr
1745 1750 1755
Cys Gln Ala Trp Ser Ser Met Thr Pro His Ser His Ser Arg Thr
1760 1765 1770
Pro Glu Tyr Tyr Pro Asn Ala Gly Leu Ile Met Asn Tyr Cys Arg
1775 1780 1785
Asn Pro Asp Ala Val Ala Ala Pro Tyr Cys Tyr Thr Arg Asp Pro
1790 1795 1800
Gly Val Arg Trp Glu Tyr Cys Asn Leu Thr Gln Cys Ser Asp Ala
1805 1810 1815
Glu Gly Thr Ala Val Ala Pro Pro Thr Val Thr Pro Val Pro Ser
1820 1825 1830
Leu Glu Ala Pro Ser Glu Gln Ala Pro Thr Glu Gln Arg Pro Gly
1835 1840 1845
Val Gln Glu Cys Tyr His Gly Asn Gly Gln Ser Tyr Arg Gly Thr
1850 1855 1860
Tyr Ser Thr Thr Val Thr Gly Arg Thr Cys Gln Ala Trp Ser Ser
1865 1870 1875
Met Thr Pro His Ser His Ser Arg Thr Pro Glu Tyr Tyr Pro Asn
1880 1885 1890
Ala Gly Leu Ile Met Asn Tyr Cys Arg Asn Pro Asp Ala Val Ala
1895 1900 1905
Ala Pro Tyr Cys Tyr Thr Arg Asp Pro Gly Val Arg Trp Glu Tyr
1910 1915 1920
Cys Asn Leu Thr Gln Cys Ser Asp Ala Glu Gly Thr Ala Val Ala
1925 1930 1935
Pro Pro Thr Val Thr Pro Val Pro Ser Leu Glu Ala Pro Ser Glu
1940 1945 1950
Gln Ala Pro Thr Glu Gln Arg Pro Gly Val Gln Glu Cys Tyr His
1955 1960 1965
Gly Asn Gly Gln Ser Tyr Arg Gly Thr Tyr Ser Thr Thr Val Thr
1970 1975 1980
Gly Arg Thr Cys Gln Ala Trp Ser Ser Met Thr Pro His Ser His
1985 1990 1995
Ser Arg Thr Pro Glu Tyr Tyr Pro Asn Ala Gly Leu Ile Met Asn
2000 2005 2010
Tyr Cys Arg Asn Pro Asp Ala Val Ala Ala Pro Tyr Cys Tyr Thr
2015 2020 2025
Arg Asp Pro Gly Val Arg Trp Glu Tyr Cys Asn Leu Thr Gln Cys
2030 2035 2040
Ser Asp Ala Glu Gly Thr Ala Val Ala Pro Pro Thr Val Thr Pro
2045 2050 2055
Val Pro Ser Leu Glu Ala Pro Ser Glu Gln Ala Pro Thr Glu Gln
2060 2065 2070
Arg Pro Gly Val Gln Glu Cys Tyr His Gly Asn Gly Gln Ser Tyr
2075 2080 2085
Arg Gly Thr Tyr Ser Thr Thr Val Thr Gly Arg Thr Cys Gln Ala
2090 2095 2100
Trp Ser Ser Met Thr Pro His Ser His Ser Arg Thr Pro Glu Tyr
2105 2110 2115
Tyr Pro Asn Ala Gly Leu Ile Met Asn Tyr Cys Arg Asn Pro Asp
2120 2125 2130
Ala Val Ala Ala Pro Tyr Cys Tyr Thr Arg Asp Pro Gly Val Arg
2135 2140 2145
Trp Glu Tyr Cys Asn Leu Thr Gln Cys Ser Asp Ala Glu Gly Thr
2150 2155 2160
Ala Val Ala Pro Pro Thr Val Thr Pro Val Pro Ser Leu Glu Ala
2165 2170 2175
Pro Ser Glu Gln Ala Pro Thr Glu Gln Arg Pro Gly Val Gln Glu
2180 2185 2190
Cys Tyr His Gly Asn Gly Gln Ser Tyr Arg Gly Thr Tyr Ser Thr
2195 2200 2205
Thr Val Thr Gly Arg Thr Cys Gln Ala Trp Ser Ser Met Thr Pro
2210 2215 2220
His Ser His Ser Arg Thr Pro Glu Tyr Tyr Pro Asn Ala Gly Leu
2225 2230 2235
Ile Met Asn Tyr Cys Arg Asn Pro Asp Ala Val Ala Ala Pro Tyr
2240 2245 2250
Cys Tyr Thr Arg Asp Pro Gly Val Arg Trp Glu Tyr Cys Asn Leu
2255 2260 2265
Thr Gln Cys Ser Asp Ala Glu Gly Thr Ala Val Ala Pro Pro Thr
2270 2275 2280
Val Thr Pro Val Pro Ser Leu Glu Ala Pro Ser Glu Gln Ala Pro
2285 2290 2295
Thr Glu Gln Arg Pro Gly Val Gln Glu Cys Tyr His Gly Asn Gly
2300 2305 2310
Gln Ser Tyr Arg Gly Thr Tyr Ser Thr Thr Val Thr Gly Arg Thr
2315 2320 2325
Cys Gln Ala Trp Ser Ser Met Thr Pro His Ser His Ser Arg Thr
2330 2335 2340
Pro Glu Tyr Tyr Pro Asn Ala Gly Leu Ile Met Asn Tyr Cys Arg
2345 2350 2355
Asn Pro Asp Ala Val Ala Ala Pro Tyr Cys Tyr Thr Arg Asp Pro
2360 2365 2370
Gly Val Arg Trp Glu Tyr Cys Asn Leu Thr Gln Cys Ser Asp Ala
2375 2380 2385
Glu Gly Thr Ala Val Ala Pro Pro Thr Val Thr Pro Val Pro Ser
2390 2395 2400
Leu Glu Ala Pro Ser Glu Gln Ala Pro Thr Glu Gln Arg Pro Gly
2405 2410 2415
Val Gln Glu Cys Tyr His Gly Asn Gly Gln Ser Tyr Arg Gly Thr
2420 2425 2430
Tyr Ser Thr Thr Val Thr Gly Arg Thr Cys Gln Ala Trp Ser Ser
2435 2440 2445
Met Thr Pro His Ser His Ser Arg Thr Pro Glu Tyr Tyr Pro Asn
2450 2455 2460
Ala Gly Leu Ile Met Asn Tyr Cys Arg Asn Pro Asp Ala Val Ala
2465 2470 2475
Ala Pro Tyr Cys Tyr Thr Arg Asp Pro Gly Val Arg Trp Glu Tyr
2480 2485 2490
Cys Asn Leu Thr Gln Cys Ser Asp Ala Glu Gly Thr Ala Val Ala
2495 2500 2505
Pro Pro Thr Val Thr Pro Val Pro Ser Leu Glu Ala Pro Ser Glu
2510 2515 2520
Gln Ala Pro Thr Glu Gln Arg Pro Gly Val Gln Glu Cys Tyr His
2525 2530 2535
Gly Asn Gly Gln Ser Tyr Arg Gly Thr Tyr Ser Thr Thr Val Thr
2540 2545 2550
Gly Arg Thr Cys Gln Ala Trp Ser Ser Met Thr Pro His Ser His
2555 2560 2565
Ser Arg Thr Pro Glu Tyr Tyr Pro Asn Ala Gly Leu Ile Met Asn
2570 2575 2580
Tyr Cys Arg Asn Pro Asp Ala Val Ala Ala Pro Tyr Cys Tyr Thr
2585 2590 2595
Arg Asp Pro Gly Val Arg Trp Glu Tyr Cys Asn Leu Thr Gln Cys
2600 2605 2610
Ser Asp Ala Glu Gly Thr Ala Val Ala Pro Pro Thr Val Thr Pro
2615 2620 2625
Val Pro Ser Leu Glu Ala Pro Ser Glu Gln Ala Pro Thr Glu Gln
2630 2635 2640
Arg Pro Gly Val Gln Glu Cys Tyr His Gly Asn Gly Gln Ser Tyr
2645 2650 2655
Arg Gly Thr Tyr Ser Thr Thr Val Thr Gly Arg Thr Cys Gln Ala
2660 2665 2670
Trp Ser Ser Met Thr Pro His Ser His Ser Arg Thr Pro Glu Tyr
2675 2680 2685
Tyr Pro Asn Ala Gly Leu Ile Met Asn Tyr Cys Arg Asn Pro Asp
2690 2695 2700
Ala Val Ala Ala Pro Tyr Cys Tyr Thr Arg Asp Pro Gly Val Arg
2705 2710 2715
Trp Glu Tyr Cys Asn Leu Thr Gln Cys Ser Asp Ala Glu Gly Thr
2720 2725 2730
Ala Val Ala Pro Pro Thr Val Thr Pro Val Pro Ser Leu Glu Ala
2735 2740 2745
Pro Ser Glu Gln Ala Pro Thr Glu Gln Arg Pro Gly Val Gln Glu
2750 2755 2760
Cys Tyr His Gly Asn Gly Gln Ser Tyr Arg Gly Thr Tyr Ser Thr
2765 2770 2775
Thr Val Thr Gly Arg Thr Cys Gln Ala Trp Ser Ser Met Thr Pro
2780 2785 2790
His Ser His Ser Arg Thr Pro Glu Tyr Tyr Pro Asn Ala Gly Leu
2795 2800 2805
Ile Met Asn Tyr Cys Arg Asn Pro Asp Ala Val Ala Ala Pro Tyr
2810 2815 2820
Cys Tyr Thr Arg Asp Pro Gly Val Arg Trp Glu Tyr Cys Asn Leu
2825 2830 2835
Thr Gln Cys Ser Asp Ala Glu Gly Thr Ala Val Ala Pro Pro Thr
2840 2845 2850
Val Thr Pro Val Pro Ser Leu Glu Ala Pro Ser Glu Gln Ala Pro
2855 2860 2865
Thr Glu Gln Arg Pro Gly Val Gln Glu Cys Tyr His Gly Asn Gly
2870 2875 2880
Gln Ser Tyr Arg Gly Thr Tyr Ser Thr Thr Val Thr Gly Arg Thr
2885 2890 2895
Cys Gln Ala Trp Ser Ser Met Thr Pro His Ser His Ser Arg Thr
2900 2905 2910
Pro Glu Tyr Tyr Pro Asn Ala Gly Leu Ile Met Asn Tyr Cys Arg
2915 2920 2925
Asn Pro Asp Ala Val Ala Ala Pro Tyr Cys Tyr Thr Arg Asp Pro
2930 2935 2940
Gly Val Arg Trp Glu Tyr Cys Asn Leu Thr Gln Cys Ser Asp Ala
2945 2950 2955
Glu Gly Thr Ala Val Ala Pro Pro Thr Val Thr Pro Val Pro Ser
2960 2965 2970
Leu Glu Ala Pro Ser Glu Gln Ala Pro Thr Glu Gln Arg Pro Gly
2975 2980 2985
Val Gln Glu Cys Tyr His Gly Asn Gly Gln Ser Tyr Arg Gly Thr
2990 2995 3000
Tyr Ser Thr Thr Val Thr Gly Arg Thr Cys Gln Ala Trp Ser Ser
3005 3010 3015
Met Thr Pro His Ser His Ser Arg Thr Pro Glu Tyr Tyr Pro Asn
3020 3025 3030
Ala Gly Leu Ile Met Asn Tyr Cys Arg Asn Pro Asp Ala Val Ala
3035 3040 3045
Ala Pro Tyr Cys Tyr Thr Arg Asp Pro Gly Val Arg Trp Glu Tyr
3050 3055 3060
Cys Asn Leu Thr Gln Cys Ser Asp Ala Glu Gly Thr Ala Val Ala
3065 3070 3075
Pro Pro Thr Val Thr Pro Val Pro Ser Leu Glu Ala Pro Ser Glu
3080 3085 3090
Gln Ala Pro Thr Glu Gln Arg Pro Gly Val Gln Glu Cys Tyr His
3095 3100 3105
Gly Asn Gly Gln Ser Tyr Arg Gly Thr Tyr Ser Thr Thr Val Thr
3110 3115 3120
Gly Arg Thr Cys Gln Ala Trp Ser Ser Met Thr Pro His Ser His
3125 3130 3135
Ser Arg Thr Pro Glu Tyr Tyr Pro Asn Ala Gly Leu Ile Met Asn
3140 3145 3150
Tyr Cys Arg Asn Pro Asp Ala Val Ala Ala Pro Tyr Cys Tyr Thr
3155 3160 3165
Arg Asp Pro Gly Val Arg Trp Glu Tyr Cys Asn Leu Thr Gln Cys
3170 3175 3180
Ser Asp Ala Glu Gly Thr Ala Val Ala Pro Pro Thr Val Thr Pro
3185 3190 3195
Val Pro Ser Leu Glu Ala Pro Ser Glu Gln Ala Pro Thr Glu Gln
3200 3205 3210
Arg Pro Gly Val Gln Glu Cys Tyr His Gly Asn Gly Gln Ser Tyr
3215 3220 3225
Arg Gly Thr Tyr Ser Thr Thr Val Thr Gly Arg Thr Cys Gln Ala
3230 3235 3240
Trp Ser Ser Met Thr Pro His Ser His Ser Arg Thr Pro Glu Tyr
3245 3250 3255
Tyr Pro Asn Ala Gly Leu Ile Met Asn Tyr Cys Arg Asn Pro Asp
3260 3265 3270
Ala Val Ala Ala Pro Tyr Cys Tyr Thr Arg Asp Pro Gly Val Arg
3275 3280 3285
Trp Glu Tyr Cys Asn Leu Thr Gln Cys Ser Asp Ala Glu Gly Thr
3290 3295 3300
Ala Val Ala Pro Pro Thr Val Thr Pro Val Pro Ser Leu Glu Ala
3305 3310 3315
Pro Ser Glu Gln Ala Pro Thr Glu Gln Arg Pro Gly Val Gln Glu
3320 3325 3330
Cys Tyr His Gly Asn Gly Gln Ser Tyr Arg Gly Thr Tyr Ser Thr
3335 3340 3345
Thr Val Thr Gly Arg Thr Cys Gln Ala Trp Ser Ser Met Thr Pro
3350 3355 3360
His Ser His Ser Arg Thr Pro Glu Tyr Tyr Pro Asn Ala Gly Leu
3365 3370 3375
Ile Met Asn Tyr Cys Arg Asn Pro Asp Pro Val Ala Ala Pro Tyr
3380 3385 3390
Cys Tyr Thr Arg Asp Pro Ser Val Arg Trp Glu Tyr Cys Asn Leu
3395 3400 3405
Thr Gln Cys Ser Asp Ala Glu Gly Thr Ala Val Ala Pro Pro Thr
3410 3415 3420
Ile Thr Pro Ile Pro Ser Leu Glu Ala Pro Ser Glu Gln Ala Pro
3425 3430 3435
Thr Glu Gln Arg Pro Gly Val Gln Glu Cys Tyr His Gly Asn Gly
3440 3445 3450
Gln Ser Tyr Gln Gly Thr Tyr Phe Ile Thr Val Thr Gly Arg Thr
3455 3460 3465
Cys Gln Ala Trp Ser Ser Met Thr Pro His Ser His Ser Arg Thr
3470 3475 3480
Pro Ala Tyr Tyr Pro Asn Ala Gly Leu Ile Lys Asn Tyr Cys Arg
3485 3490 3495
Asn Pro Asp Pro Val Ala Ala Pro Trp Cys Tyr Thr Thr Asp Pro
3500 3505 3510
Ser Val Arg Trp Glu Tyr Cys Asn Leu Thr Arg Cys Ser Asp Ala
3515 3520 3525
Glu Trp Thr Ala Phe Val Pro Pro Asn Val Ile Leu Ala Pro Ser
3530 3535 3540
Leu Glu Ala Phe Phe Glu Gln Ala Leu Thr Glu Glu Thr Pro Gly
3545 3550 3555
Val Gln Asp Cys Tyr Tyr His Tyr Gly Gln Ser Tyr Arg Gly Thr
3560 3565 3570
Tyr Ser Thr Thr Val Thr Gly Arg Thr Cys Gln Ala Trp Ser Ser
3575 3580 3585
Met Thr Pro His Gln His Ser Arg Thr Pro Glu Asn Tyr Pro Asn
3590 3595 3600
Ala Gly Leu Thr Arg Asn Tyr Cys Arg Asn Pro Asp Ala Glu Ile
3605 3610 3615
Arg Pro Trp Cys Tyr Thr Met Asp Pro Ser Val Arg Trp Glu Tyr
3620 3625 3630
Cys Asn Leu Thr Gln Cys Leu Val Thr Glu Ser Ser Val Leu Ala
3635 3640 3645
Thr Leu Thr Val Val Pro Asp Pro Ser Thr Glu Ala Ser Ser Glu
3650 3655 3660
Glu Ala Pro Thr Glu Gln Ser Pro Gly Val Gln Asp Cys Tyr His
3665 3670 3675
Gly Asp Gly Gln Ser Tyr Arg Gly Ser Phe Ser Thr Thr Val Thr
3680 3685 3690
Gly Arg Thr Cys Gln Ser Trp Ser Ser Met Thr Pro His Trp His
3695 3700 3705
Gln Arg Thr Thr Glu Tyr Tyr Pro Asn Gly Gly Leu Thr Arg Asn
3710 3715 3720
Tyr Cys Arg Asn Pro Asp Ala Glu Ile Ser Pro Trp Cys Tyr Thr
3725 3730 3735
Met Asp Pro Asn Val Arg Trp Glu Tyr Cys Asn Leu Thr Gln Cys
3740 3745 3750
Pro Val Thr Glu Ser Ser Val Leu Ala Thr Ser Thr Ala Val Ser
3755 3760 3765
Glu Gln Ala Pro Thr Glu Gln Ser Pro Thr Val Gln Asp Cys Tyr
3770 3775 3780
His Gly Asp Gly Gln Ser Tyr Arg Gly Ser Phe Ser Thr Thr Val
3785 3790 3795
Thr Gly Arg Thr Cys Gln Ser Trp Ser Ser Met Thr Pro His Trp
3800 3805 3810
His Gln Arg Thr Thr Glu Tyr Tyr Pro Asn Gly Gly Leu Thr Arg
3815 3820 3825
Asn Tyr Cys Arg Asn Pro Asp Ala Glu Ile Arg Pro Trp Cys Tyr
3830 3835 3840
Thr Met Asp Pro Ser Val Arg Trp Glu Tyr Cys Asn Leu Thr Gln
3845 3850 3855
Cys Pro Val Met Glu Ser Thr Leu Leu Thr Thr Pro Thr Val Val
3860 3865 3870
Pro Val Pro Ser Thr Glu Leu Pro Ser Glu Glu Ala Pro Thr Glu
3875 3880 3885
Asn Ser Thr Gly Val Gln Asp Cys Tyr Arg Gly Asp Gly Gln Ser
3890 3895 3900
Tyr Arg Gly Thr Leu Ser Thr Thr Ile Thr Gly Arg Thr Cys Gln
3905 3910 3915
Ser Trp Ser Ser Met Thr Pro His Trp His Arg Arg Ile Pro Leu
3920 3925 3930
Tyr Tyr Pro Asn Ala Gly Leu Thr Arg Asn Tyr Cys Arg Asn Pro
3935 3940 3945
Asp Ala Glu Ile Arg Pro Trp Cys Tyr Thr Met Asp Pro Ser Val
3950 3955 3960
Arg Trp Glu Tyr Cys Asn Leu Thr Arg Cys Pro Val Thr Glu Ser
3965 3970 3975
Ser Val Leu Thr Thr Pro Thr Val Ala Pro Val Pro Ser Thr Glu
3980 3985 3990
Ala Pro Ser Glu Gln Ala Pro Pro Glu Lys Ser Pro Val Val Gln
3995 4000 4005
Asp Cys Tyr His Gly Asp Gly Arg Ser Tyr Arg Gly Ile Ser Ser
4010 4015 4020
Thr Thr Val Thr Gly Arg Thr Cys Gln Ser Trp Ser Ser Met Ile
4025 4030 4035
Pro His Trp His Gln Arg Thr Pro Glu Asn Tyr Pro Asn Ala Gly
4040 4045 4050
Leu Thr Glu Asn Tyr Cys Arg Asn Pro Asp Ser Gly Lys Gln Pro
4055 4060 4065
Trp Cys Tyr Thr Thr Asp Pro Cys Val Arg Trp Glu Tyr Cys Asn
4070 4075 4080
Leu Thr Gln Cys Ser Glu Thr Glu Ser Gly Val Leu Glu Thr Pro
4085 4090 4095
Thr Val Val Pro Val Pro Ser Met Glu Ala His Ser Glu Ala Ala
4100 4105 4110
Pro Thr Glu Gln Thr Pro Val Val Arg Gln Cys Tyr His Gly Asn
4115 4120 4125
Gly Gln Ser Tyr Arg Gly Thr Phe Ser Thr Thr Val Thr Gly Arg
4130 4135 4140
Thr Cys Gln Ser Trp Ser Ser Met Thr Pro His Arg His Gln Arg
4145 4150 4155
Thr Pro Glu Asn Tyr Pro Asn Asp Gly Leu Thr Met Asn Tyr Cys
4160 4165 4170
Arg Asn Pro Asp Ala Asp Thr Gly Pro Trp Cys Phe Thr Met Asp
4175 4180 4185
Pro Ser Ile Arg Trp Glu Tyr Cys Asn Leu Thr Arg Cys Ser Asp
4190 4195 4200
Thr Glu Gly Thr Val Val Ala Pro Pro Thr Val Ile Gln Val Pro
4205 4210 4215
Ser Leu Gly Pro Pro Ser Glu Gln Asp Cys Met Phe Gly Asn Gly
4220 4225 4230
Lys Gly Tyr Arg Gly Lys Lys Ala Thr Thr Val Thr Gly Thr Pro
4235 4240 4245
Cys Gln Glu Trp Ala Ala Gln Glu Pro His Arg His Ser Thr Phe
4250 4255 4260
Ile Pro Gly Thr Asn Lys Trp Ala Gly Leu Glu Lys Asn Tyr Cys
4265 4270 4275
Arg Asn Pro Asp Gly Asp Ile Asn Gly Pro Trp Cys Tyr Thr Met
4280 4285 4290
Asn Pro Arg Lys Leu Phe Asp Tyr Cys Asp Ile Pro Leu Cys Ala
4295 4300 4305
Ser Ser Ser Phe Asp Cys Gly Lys Pro Gln Val Glu Pro Lys Lys
4310 4315 4320
Cys Pro Gly Ser Ile Val Gly Gly Cys Val Ala His Pro His Ser
4325 4330 4335
Trp Pro Trp Gln Val Ser Leu Arg Thr Arg Phe Gly Lys His Phe
4340 4345 4350
Cys Gly Gly Thr Leu Ile Ser Pro Glu Trp Val Leu Thr Ala Ala
4355 4360 4365
His Cys Leu Lys Lys Ser Ser Arg Pro Ser Ser Tyr Lys Val Ile
4370 4375 4380
Leu Gly Ala His Gln Glu Val Asn Leu Glu Ser His Val Gln Glu
4385 4390 4395
Ile Glu Val Ser Arg Leu Phe Leu Glu Pro Thr Gln Ala Asp Ile
4400 4405 4410
Ala Leu Leu Lys Leu Ser Arg Pro Ala Val Ile Thr Asp Lys Val
4415 4420 4425
Met Pro Ala Cys Leu Pro Ser Pro Asp Tyr Met Val Thr Ala Arg
4430 4435 4440
Thr Glu Cys Tyr Ile Thr Gly Trp Gly Glu Thr Gln Gly Thr Phe
4445 4450 4455
Gly Thr Gly Leu Leu Lys Glu Ala Gln Leu Leu Val Ile Glu Asn
4460 4465 4470
Glu Val Cys Asn His Tyr Lys Tyr Ile Cys Ala Glu His Leu Ala
4475 4480 4485
Arg Gly Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val
4490 4495 4500
Cys Phe Glu Lys Asp Lys Tyr Ile Leu Gln Gly Val Thr Ser Trp
4505 4510 4515
Gly Leu Gly Cys Ala Arg Pro Asn Lys Pro Gly Val Tyr Ala Arg
4520 4525 4530
Val Ser Arg Phe Val Thr Trp Ile Glu Gly Met Met Arg Asn Asn
4535 4540 4545
<210> 4
<211> 911
<212> PRT
<213> 智人(Homo sapiens)
<220>
<221> 人间α胰蛋白酶抑制剂重链 H1 (ITIH1)
<222> (1)..(911)
<400> 4
Met Asp Gly Ala Met Gly Pro Arg Gly Leu Leu Leu Cys Met Tyr Leu
1 5 10 15
Val Ser Leu Leu Ile Leu Gln Ala Met Pro Ala Leu Gly Ser Ala Thr
20 25 30
Gly Arg Ser Lys Ser Ser Glu Lys Arg Gln Ala Val Asp Thr Ala Val
35 40 45
Asp Gly Val Phe Ile Arg Ser Leu Lys Val Asn Cys Lys Val Thr Ser
50 55 60
Arg Phe Ala His Tyr Val Val Thr Ser Gln Val Val Asn Thr Ala Asn
65 70 75 80
Glu Ala Arg Glu Val Ala Phe Asp Leu Glu Ile Pro Lys Thr Ala Phe
85 90 95
Ile Ser Asp Phe Ala Val Thr Ala Asp Gly Asn Ala Phe Ile Gly Asp
100 105 110
Ile Lys Asp Lys Val Thr Ala Trp Lys Gln Tyr Arg Lys Ala Ala Ile
115 120 125
Ser Gly Glu Asn Ala Gly Leu Val Arg Ala Ser Gly Arg Thr Met Glu
130 135 140
Gln Phe Thr Ile His Leu Thr Val Asn Pro Gln Ser Lys Val Thr Phe
145 150 155 160
Gln Leu Thr Tyr Glu Glu Val Leu Lys Arg Asn His Met Gln Tyr Glu
165 170 175
Ile Val Ile Lys Val Lys Pro Lys Gln Leu Val His His Phe Glu Ile
180 185 190
Asp Val Asp Ile Phe Glu Pro Gln Gly Ile Ser Lys Leu Asp Ala Gln
195 200 205
Ala Ser Phe Leu Pro Lys Glu Leu Ala Ala Gln Thr Ile Lys Lys Ser
210 215 220
Phe Ser Gly Lys Lys Gly His Val Leu Phe Arg Pro Thr Val Ser Gln
225 230 235 240
Gln Gln Ser Cys Pro Thr Cys Ser Thr Ser Leu Leu Asn Gly His Phe
245 250 255
Lys Val Thr Tyr Asp Val Ser Arg Asp Lys Ile Cys Asp Leu Leu Val
260 265 270
Ala Asn Asn His Phe Ala His Phe Phe Ala Pro Gln Asn Leu Thr Asn
275 280 285
Met Asn Lys Asn Val Val Phe Val Ile Asp Ile Ser Gly Ser Met Arg
290 295 300
Gly Gln Lys Val Lys Gln Thr Lys Glu Ala Leu Leu Lys Ile Leu Gly
305 310 315 320
Asp Met Gln Pro Gly Asp Tyr Phe Asp Leu Val Leu Phe Gly Thr Arg
325 330 335
Val Gln Ser Trp Lys Gly Ser Leu Val Gln Ala Ser Glu Ala Asn Leu
340 345 350
Gln Ala Ala Gln Asp Phe Val Arg Gly Phe Ser Leu Asp Glu Ala Thr
355 360 365
Asn Leu Asn Gly Gly Leu Leu Arg Gly Ile Glu Ile Leu Asn Gln Val
370 375 380
Gln Glu Ser Leu Pro Glu Leu Ser Asn His Ala Ser Ile Leu Ile Met
385 390 395 400
Leu Thr Asp Gly Asp Pro Thr Glu Gly Val Thr Asp Arg Ser Gln Ile
405 410 415
Leu Lys Asn Val Arg Asn Ala Ile Arg Gly Arg Phe Pro Leu Tyr Asn
420 425 430
Leu Gly Phe Gly His Asn Val Asp Phe Asn Phe Leu Glu Val Met Ser
435 440 445
Met Glu Asn Asn Gly Arg Ala Gln Arg Ile Tyr Glu Asp His Asp Ala
450 455 460
Thr Gln Gln Leu Gln Gly Phe Tyr Ser Gln Val Ala Lys Pro Leu Leu
465 470 475 480
Val Asp Val Asp Leu Gln Tyr Pro Gln Asp Ala Val Leu Ala Leu Thr
485 490 495
Gln Asn His His Lys Gln Tyr Tyr Glu Gly Ser Glu Ile Val Val Ala
500 505 510
Gly Arg Ile Ala Asp Asn Lys Gln Ser Ser Phe Lys Ala Asp Val Gln
515 520 525
Ala His Gly Glu Gly Gln Glu Phe Ser Ile Thr Cys Leu Val Asp Glu
530 535 540
Glu Glu Met Lys Lys Leu Leu Arg Glu Arg Gly His Met Leu Glu Asn
545 550 555 560
His Val Glu Arg Leu Trp Ala Tyr Leu Thr Ile Gln Glu Leu Leu Ala
565 570 575
Lys Arg Met Lys Val Asp Arg Glu Glu Arg Ala Asn Leu Ser Ser Gln
580 585 590
Ala Leu Gln Met Ser Leu Asp Tyr Gly Phe Val Thr Pro Leu Thr Ser
595 600 605
Met Ser Ile Arg Gly Met Ala Asp Gln Asp Gly Leu Lys Pro Thr Ile
610 615 620
Asp Lys Pro Ser Glu Asp Ser Pro Pro Leu Glu Met Leu Gly Pro Arg
625 630 635 640
Arg Thr Phe Val Leu Ser Ala Leu Gln Pro Ser Pro Thr His Ser Ser
645 650 655
Ser Asn Thr Gln Arg Leu Pro Asp Arg Val Thr Gly Val Asp Thr Asp
660 665 670
Pro His Phe Ile Ile His Val Pro Gln Lys Glu Asp Thr Leu Cys Phe
675 680 685
Asn Ile Asn Glu Glu Pro Gly Val Ile Leu Ser Leu Val Gln Asp Pro
690 695 700
Asn Thr Gly Phe Ser Val Asn Gly Gln Leu Ile Gly Asn Lys Ala Arg
705 710 715 720
Ser Pro Gly Gln His Asp Gly Thr Tyr Phe Gly Arg Leu Gly Ile Ala
725 730 735
Asn Pro Ala Thr Asp Phe Gln Leu Glu Val Thr Pro Gln Asn Ile Thr
740 745 750
Leu Asn Pro Gly Phe Gly Gly Pro Val Phe Ser Trp Arg Asp Gln Ala
755 760 765
Val Leu Arg Gln Asp Gly Val Val Val Thr Ile Asn Lys Lys Arg Asn
770 775 780
Leu Val Val Ser Val Asp Asp Gly Gly Thr Phe Glu Val Val Leu His
785 790 795 800
Arg Val Trp Lys Gly Ser Ser Val His Gln Asp Phe Leu Gly Phe Tyr
805 810 815
Val Leu Asp Ser His Arg Met Ser Ala Arg Thr His Gly Leu Leu Gly
820 825 830
Gln Phe Phe His Pro Ile Gly Phe Glu Val Ser Asp Ile His Pro Gly
835 840 845
Ser Asp Pro Thr Lys Pro Asp Ala Thr Met Val Val Arg Asn Arg Arg
850 855 860
Leu Thr Val Thr Arg Gly Leu Gln Lys Asp Tyr Ser Lys Asp Pro Trp
865 870 875 880
His Gly Ala Glu Val Ser Cys Trp Phe Ile His Asn Asn Gly Ala Gly
885 890 895
Leu Ile Asp Gly Ala Tyr Thr Asp Tyr Ile Val Pro Asp Ile Phe
900 905 910
<210> 5
<211> 1676
<212> PRT
<213> 智人(Homo sapiens)
<220>
<221> 人补体组分C5
<222> (1)..(1676)
<400> 5
Met Gly Leu Leu Gly Ile Leu Cys Phe Leu Ile Phe Leu Gly Lys Thr
1 5 10 15
Trp Gly Gln Glu Gln Thr Tyr Val Ile Ser Ala Pro Lys Ile Phe Arg
20 25 30
Val Gly Ala Ser Glu Asn Ile Val Ile Gln Val Tyr Gly Tyr Thr Glu
35 40 45
Ala Phe Asp Ala Thr Ile Ser Ile Lys Ser Tyr Pro Asp Lys Lys Phe
50 55 60
Ser Tyr Ser Ser Gly His Val His Leu Ser Ser Glu Asn Lys Phe Gln
65 70 75 80
Asn Ser Ala Ile Leu Thr Ile Gln Pro Lys Gln Leu Pro Gly Gly Gln
85 90 95
Asn Pro Val Ser Tyr Val Tyr Leu Glu Val Val Ser Lys His Phe Ser
100 105 110
Lys Ser Lys Arg Met Pro Ile Thr Tyr Asp Asn Gly Phe Leu Phe Ile
115 120 125
His Thr Asp Lys Pro Val Tyr Thr Pro Asp Gln Ser Val Lys Val Arg
130 135 140
Val Tyr Ser Leu Asn Asp Asp Leu Lys Pro Ala Lys Arg Glu Thr Val
145 150 155 160
Leu Thr Phe Ile Asp Pro Glu Gly Ser Glu Val Asp Met Val Glu Glu
165 170 175
Ile Asp His Ile Gly Ile Ile Ser Phe Pro Asp Phe Lys Ile Pro Ser
180 185 190
Asn Pro Arg Tyr Gly Met Trp Thr Ile Lys Ala Lys Tyr Lys Glu Asp
195 200 205
Phe Ser Thr Thr Gly Thr Ala Tyr Phe Glu Val Lys Glu Tyr Val Leu
210 215 220
Pro His Phe Ser Val Ser Ile Glu Pro Glu Tyr Asn Phe Ile Gly Tyr
225 230 235 240
Lys Asn Phe Lys Asn Phe Glu Ile Thr Ile Lys Ala Arg Tyr Phe Tyr
245 250 255
Asn Lys Val Val Thr Glu Ala Asp Val Tyr Ile Thr Phe Gly Ile Arg
260 265 270
Glu Asp Leu Lys Asp Asp Gln Lys Glu Met Met Gln Thr Ala Met Gln
275 280 285
Asn Thr Met Leu Ile Asn Gly Ile Ala Gln Val Thr Phe Asp Ser Glu
290 295 300
Thr Ala Val Lys Glu Leu Ser Tyr Tyr Ser Leu Glu Asp Leu Asn Asn
305 310 315 320
Lys Tyr Leu Tyr Ile Ala Val Thr Val Ile Glu Ser Thr Gly Gly Phe
325 330 335
Ser Glu Glu Ala Glu Ile Pro Gly Ile Lys Tyr Val Leu Ser Pro Tyr
340 345 350
Lys Leu Asn Leu Val Ala Thr Pro Leu Phe Leu Lys Pro Gly Ile Pro
355 360 365
Tyr Pro Ile Lys Val Gln Val Lys Asp Ser Leu Asp Gln Leu Val Gly
370 375 380
Gly Val Pro Val Thr Leu Asn Ala Gln Thr Ile Asp Val Asn Gln Glu
385 390 395 400
Thr Ser Asp Leu Asp Pro Ser Lys Ser Val Thr Arg Val Asp Asp Gly
405 410 415
Val Ala Ser Phe Val Leu Asn Leu Pro Ser Gly Val Thr Val Leu Glu
420 425 430
Phe Asn Val Lys Thr Asp Ala Pro Asp Leu Pro Glu Glu Asn Gln Ala
435 440 445
Arg Glu Gly Tyr Arg Ala Ile Ala Tyr Ser Ser Leu Ser Gln Ser Tyr
450 455 460
Leu Tyr Ile Asp Trp Thr Asp Asn His Lys Ala Leu Leu Val Gly Glu
465 470 475 480
His Leu Asn Ile Ile Val Thr Pro Lys Ser Pro Tyr Ile Asp Lys Ile
485 490 495
Thr His Tyr Asn Tyr Leu Ile Leu Ser Lys Gly Lys Ile Ile His Phe
500 505 510
Gly Thr Arg Glu Lys Phe Ser Asp Ala Ser Tyr Gln Ser Ile Asn Ile
515 520 525
Pro Val Thr Gln Asn Met Val Pro Ser Ser Arg Leu Leu Val Tyr Tyr
530 535 540
Ile Val Thr Gly Glu Gln Thr Ala Glu Leu Val Ser Asp Ser Val Trp
545 550 555 560
Leu Asn Ile Glu Glu Lys Cys Gly Asn Gln Leu Gln Val His Leu Ser
565 570 575
Pro Asp Ala Asp Ala Tyr Ser Pro Gly Gln Thr Val Ser Leu Asn Met
580 585 590
Ala Thr Gly Met Asp Ser Trp Val Ala Leu Ala Ala Val Asp Ser Ala
595 600 605
Val Tyr Gly Val Gln Arg Gly Ala Lys Lys Pro Leu Glu Arg Val Phe
610 615 620
Gln Phe Leu Glu Lys Ser Asp Leu Gly Cys Gly Ala Gly Gly Gly Leu
625 630 635 640
Asn Asn Ala Asn Val Phe His Leu Ala Gly Leu Thr Phe Leu Thr Asn
645 650 655
Ala Asn Ala Asp Asp Ser Gln Glu Asn Asp Glu Pro Cys Lys Glu Ile
660 665 670
Leu Arg Pro Arg Arg Thr Leu Gln Lys Lys Ile Glu Glu Ile Ala Ala
675 680 685
Lys Tyr Lys His Ser Val Val Lys Lys Cys Cys Tyr Asp Gly Ala Cys
690 695 700
Val Asn Asn Asp Glu Thr Cys Glu Gln Arg Ala Ala Arg Ile Ser Leu
705 710 715 720
Gly Pro Arg Cys Ile Lys Ala Phe Thr Glu Cys Cys Val Val Ala Ser
725 730 735
Gln Leu Arg Ala Asn Ile Ser His Lys Asp Met Gln Leu Gly Arg Leu
740 745 750
His Met Lys Thr Leu Leu Pro Val Ser Lys Pro Glu Ile Arg Ser Tyr
755 760 765
Phe Pro Glu Ser Trp Leu Trp Glu Val His Leu Val Pro Arg Arg Lys
770 775 780
Gln Leu Gln Phe Ala Leu Pro Asp Ser Leu Thr Thr Trp Glu Ile Gln
785 790 795 800
Gly Val Gly Ile Ser Asn Thr Gly Ile Cys Val Ala Asp Thr Val Lys
805 810 815
Ala Lys Val Phe Lys Asp Val Phe Leu Glu Met Asn Ile Pro Tyr Ser
820 825 830
Val Val Arg Gly Glu Gln Ile Gln Leu Lys Gly Thr Val Tyr Asn Tyr
835 840 845
Arg Thr Ser Gly Met Gln Phe Cys Val Lys Met Ser Ala Val Glu Gly
850 855 860
Ile Cys Thr Ser Glu Ser Pro Val Ile Asp His Gln Gly Thr Lys Ser
865 870 875 880
Ser Lys Cys Val Arg Gln Lys Val Glu Gly Ser Ser Ser His Leu Val
885 890 895
Thr Phe Thr Val Leu Pro Leu Glu Ile Gly Leu His Asn Ile Asn Phe
900 905 910
Ser Leu Glu Thr Trp Phe Gly Lys Glu Ile Leu Val Lys Thr Leu Arg
915 920 925
Val Val Pro Glu Gly Val Lys Arg Glu Ser Tyr Ser Gly Val Thr Leu
930 935 940
Asp Pro Arg Gly Ile Tyr Gly Thr Ile Ser Arg Arg Lys Glu Phe Pro
945 950 955 960
Tyr Arg Ile Pro Leu Asp Leu Val Pro Lys Thr Glu Ile Lys Arg Ile
965 970 975
Leu Ser Val Lys Gly Leu Leu Val Gly Glu Ile Leu Ser Ala Val Leu
980 985 990
Ser Gln Glu Gly Ile Asn Ile Leu Thr His Leu Pro Lys Gly Ser Ala
995 1000 1005
Glu Ala Glu Leu Met Ser Val Val Pro Val Phe Tyr Val Phe His
1010 1015 1020
Tyr Leu Glu Thr Gly Asn His Trp Asn Ile Phe His Ser Asp Pro
1025 1030 1035
Leu Ile Glu Lys Gln Lys Leu Lys Lys Lys Leu Lys Glu Gly Met
1040 1045 1050
Leu Ser Ile Met Ser Tyr Arg Asn Ala Asp Tyr Ser Tyr Ser Val
1055 1060 1065
Trp Lys Gly Gly Ser Ala Ser Thr Trp Leu Thr Ala Phe Ala Leu
1070 1075 1080
Arg Val Leu Gly Gln Val Asn Lys Tyr Val Glu Gln Asn Gln Asn
1085 1090 1095
Ser Ile Cys Asn Ser Leu Leu Trp Leu Val Glu Asn Tyr Gln Leu
1100 1105 1110
Asp Asn Gly Ser Phe Lys Glu Asn Ser Gln Tyr Gln Pro Ile Lys
1115 1120 1125
Leu Gln Gly Thr Leu Pro Val Glu Ala Arg Glu Asn Ser Leu Tyr
1130 1135 1140
Leu Thr Ala Phe Thr Val Ile Gly Ile Arg Lys Ala Phe Asp Ile
1145 1150 1155
Cys Pro Leu Val Lys Ile Asp Thr Ala Leu Ile Lys Ala Asp Asn
1160 1165 1170
Phe Leu Leu Glu Asn Thr Leu Pro Ala Gln Ser Thr Phe Thr Leu
1175 1180 1185
Ala Ile Ser Ala Tyr Ala Leu Ser Leu Gly Asp Lys Thr His Pro
1190 1195 1200
Gln Phe Arg Ser Ile Val Ser Ala Leu Lys Arg Glu Ala Leu Val
1205 1210 1215
Lys Gly Asn Pro Pro Ile Tyr Arg Phe Trp Lys Asp Asn Leu Gln
1220 1225 1230
His Lys Asp Ser Ser Val Pro Asn Thr Gly Thr Ala Arg Met Val
1235 1240 1245
Glu Thr Thr Ala Tyr Ala Leu Leu Thr Ser Leu Asn Leu Lys Asp
1250 1255 1260
Ile Asn Tyr Val Asn Pro Val Ile Lys Trp Leu Ser Glu Glu Gln
1265 1270 1275
Arg Tyr Gly Gly Gly Phe Tyr Ser Thr Gln Asp Thr Ile Asn Ala
1280 1285 1290
Ile Glu Gly Leu Thr Glu Tyr Ser Leu Leu Val Lys Gln Leu Arg
1295 1300 1305
Leu Ser Met Asp Ile Asp Val Ser Tyr Lys His Lys Gly Ala Leu
1310 1315 1320
His Asn Tyr Lys Met Thr Asp Lys Asn Phe Leu Gly Arg Pro Val
1325 1330 1335
Glu Val Leu Leu Asn Asp Asp Leu Ile Val Ser Thr Gly Phe Gly
1340 1345 1350
Ser Gly Leu Ala Thr Val His Val Thr Thr Val Val His Lys Thr
1355 1360 1365
Ser Thr Ser Glu Glu Val Cys Ser Phe Tyr Leu Lys Ile Asp Thr
1370 1375 1380
Gln Asp Ile Glu Ala Ser His Tyr Arg Gly Tyr Gly Asn Ser Asp
1385 1390 1395
Tyr Lys Arg Ile Val Ala Cys Ala Ser Tyr Lys Pro Ser Arg Glu
1400 1405 1410
Glu Ser Ser Ser Gly Ser Ser His Ala Val Met Asp Ile Ser Leu
1415 1420 1425
Pro Thr Gly Ile Ser Ala Asn Glu Glu Asp Leu Lys Ala Leu Val
1430 1435 1440
Glu Gly Val Asp Gln Leu Phe Thr Asp Tyr Gln Ile Lys Asp Gly
1445 1450 1455
His Val Ile Leu Gln Leu Asn Ser Ile Pro Ser Ser Asp Phe Leu
1460 1465 1470
Cys Val Arg Phe Arg Ile Phe Glu Leu Phe Glu Val Gly Phe Leu
1475 1480 1485
Ser Pro Ala Thr Phe Thr Val Tyr Glu Tyr His Arg Pro Asp Lys
1490 1495 1500
Gln Cys Thr Met Phe Tyr Ser Thr Ser Asn Ile Lys Ile Gln Lys
1505 1510 1515
Val Cys Glu Gly Ala Ala Cys Lys Cys Val Glu Ala Asp Cys Gly
1520 1525 1530
Gln Met Gln Glu Glu Leu Asp Leu Thr Ile Ser Ala Glu Thr Arg
1535 1540 1545
Lys Gln Thr Ala Cys Lys Pro Glu Ile Ala Tyr Ala Tyr Lys Val
1550 1555 1560
Ser Ile Thr Ser Ile Thr Val Glu Asn Val Phe Val Lys Tyr Lys
1565 1570 1575
Ala Thr Leu Leu Asp Ile Tyr Lys Thr Gly Glu Ala Val Ala Glu
1580 1585 1590
Lys Asp Ser Glu Ile Thr Phe Ile Lys Lys Val Thr Cys Thr Asn
1595 1600 1605
Ala Glu Leu Val Lys Gly Arg Gln Tyr Leu Ile Met Gly Lys Glu
1610 1615 1620
Ala Leu Gln Ile Lys Tyr Asn Phe Ser Phe Arg Tyr Ile Tyr Pro
1625 1630 1635
Leu Asp Ser Leu Thr Trp Ile Glu Tyr Trp Pro Arg Asp Thr Thr
1640 1645 1650
Cys Ser Ser Cys Gln Ala Phe Leu Ala Asn Leu Asp Glu Phe Ala
1655 1660 1665
Glu Asp Ile Phe Leu Asn Gly Cys
1670 1675
<210> 6
<211> 353
<212> PRT
<213> 智人(Homo sapiens)
<220>
<221> 人免疫球蛋白重链恒定区α1 (IGHA1)
<222> (1)..(353)
<400> 6
Ala Ser Pro Thr Ser Pro Lys Val Phe Pro Leu Ser Leu Cys Ser Thr
1 5 10 15
Gln Pro Asp Gly Asn Val Val Ile Ala Cys Leu Val Gln Gly Phe Phe
20 25 30
Pro Gln Glu Pro Leu Ser Val Thr Trp Ser Glu Ser Gly Gln Gly Val
35 40 45
Thr Ala Arg Asn Phe Pro Pro Ser Gln Asp Ala Ser Gly Asp Leu Tyr
50 55 60
Thr Thr Ser Ser Gln Leu Thr Leu Pro Ala Thr Gln Cys Leu Ala Gly
65 70 75 80
Lys Ser Val Thr Cys His Val Lys His Tyr Thr Asn Pro Ser Gln Asp
85 90 95
Val Thr Val Pro Cys Pro Val Pro Ser Thr Pro Pro Thr Pro Ser Pro
100 105 110
Ser Thr Pro Pro Thr Pro Ser Pro Ser Cys Cys His Pro Arg Leu Ser
115 120 125
Leu His Arg Pro Ala Leu Glu Asp Leu Leu Leu Gly Ser Glu Ala Asn
130 135 140
Leu Thr Cys Thr Leu Thr Gly Leu Arg Asp Ala Ser Gly Val Thr Phe
145 150 155 160
Thr Trp Thr Pro Ser Ser Gly Lys Ser Ala Val Gln Gly Pro Pro Glu
165 170 175
Arg Asp Leu Cys Gly Cys Tyr Ser Val Ser Ser Val Leu Pro Gly Cys
180 185 190
Ala Glu Pro Trp Asn His Gly Lys Thr Phe Thr Cys Thr Ala Ala Tyr
195 200 205
Pro Glu Ser Lys Thr Pro Leu Thr Ala Thr Leu Ser Lys Ser Gly Asn
210 215 220
Thr Phe Arg Pro Glu Val His Leu Leu Pro Pro Pro Ser Glu Glu Leu
225 230 235 240
Ala Leu Asn Glu Leu Val Thr Leu Thr Cys Leu Ala Arg Gly Phe Ser
245 250 255
Pro Lys Asp Val Leu Val Arg Trp Leu Gln Gly Ser Gln Glu Leu Pro
260 265 270
Arg Glu Lys Tyr Leu Thr Trp Ala Ser Arg Gln Glu Pro Ser Gln Gly
275 280 285
Thr Thr Thr Phe Ala Val Thr Ser Ile Leu Arg Val Ala Ala Glu Asp
290 295 300
Trp Lys Lys Gly Asp Thr Phe Ser Cys Met Val Gly His Glu Ala Leu
305 310 315 320
Pro Leu Ala Phe Thr Gln Lys Thr Ile Asp Arg Leu Ala Gly Lys Pro
325 330 335
Thr His Val Asn Val Ser Val Val Met Ala Glu Val Asp Gly Thr Cys
340 345 350
Tyr
<210> 7
<211> 330
<212> PRT
<213> 智人(Homo sapiens)
<220>
<221> 人免疫球蛋白重链恒定区γ1 (IGHG1)
<222> (1)..(330)
<400> 7
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 8
<211> 326
<212> PRT
<213> 智人(Homo sapiens)
<220>
<221> 人免疫球蛋白重链恒定区γ2 (IGHG2)
<222> (1)..(326)
<400> 8
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165 170 175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195 200 205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ser Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly Lys
325
<210> 9
<211> 406
<212> PRT
<213> 智人(Homo sapiens)
<220>
<221> 人触珠蛋白 (HPT)
<222> (1)..(406)
<400> 9
Met Ser Ala Leu Gly Ala Val Ile Ala Leu Leu Leu Trp Gly Gln Leu
1 5 10 15
Phe Ala Val Asp Ser Gly Asn Asp Val Thr Asp Ile Ala Asp Asp Gly
20 25 30
Cys Pro Lys Pro Pro Glu Ile Ala His Gly Tyr Val Glu His Ser Val
35 40 45
Arg Tyr Gln Cys Lys Asn Tyr Tyr Lys Leu Arg Thr Glu Gly Asp Gly
50 55 60
Val Tyr Thr Leu Asn Asp Lys Lys Gln Trp Ile Asn Lys Ala Val Gly
65 70 75 80
Asp Lys Leu Pro Glu Cys Glu Ala Asp Asp Gly Cys Pro Lys Pro Pro
85 90 95
Glu Ile Ala His Gly Tyr Val Glu His Ser Val Arg Tyr Gln Cys Lys
100 105 110
Asn Tyr Tyr Lys Leu Arg Thr Glu Gly Asp Gly Val Tyr Thr Leu Asn
115 120 125
Asn Glu Lys Gln Trp Ile Asn Lys Ala Val Gly Asp Lys Leu Pro Glu
130 135 140
Cys Glu Ala Val Cys Gly Lys Pro Lys Asn Pro Ala Asn Pro Val Gln
145 150 155 160
Arg Ile Leu Gly Gly His Leu Asp Ala Lys Gly Ser Phe Pro Trp Gln
165 170 175
Ala Lys Met Val Ser His His Asn Leu Thr Thr Gly Ala Thr Leu Ile
180 185 190
Asn Glu Gln Trp Leu Leu Thr Thr Ala Lys Asn Leu Phe Leu Asn His
195 200 205
Ser Glu Asn Ala Thr Ala Lys Asp Ile Ala Pro Thr Leu Thr Leu Tyr
210 215 220
Val Gly Lys Lys Gln Leu Val Glu Ile Glu Lys Val Val Leu His Pro
225 230 235 240
Asn Tyr Ser Gln Val Asp Ile Gly Leu Ile Lys Leu Lys Gln Lys Val
245 250 255
Ser Val Asn Glu Arg Val Met Pro Ile Cys Leu Pro Ser Lys Asp Tyr
260 265 270
Ala Glu Val Gly Arg Val Gly Tyr Val Ser Gly Trp Gly Arg Asn Ala
275 280 285
Asn Phe Lys Phe Thr Asp His Leu Lys Tyr Val Met Leu Pro Val Ala
290 295 300
Asp Gln Asp Gln Cys Ile Arg His Tyr Glu Gly Ser Thr Val Pro Glu
305 310 315 320
Lys Lys Thr Pro Lys Ser Pro Val Gly Val Gln Pro Ile Leu Asn Glu
325 330 335
His Thr Phe Cys Ala Gly Met Ser Lys Tyr Gln Glu Asp Thr Cys Tyr
340 345 350
Gly Asp Ala Gly Ser Ala Phe Ala Val His Asp Leu Glu Glu Asp Thr
355 360 365
Trp Tyr Ala Thr Gly Ile Leu Ser Phe Asp Lys Ser Cys Ala Val Ala
370 375 380
Glu Tyr Gly Val Tyr Val Lys Val Thr Ser Ile Gln Asp Trp Val Gln
385 390 395 400
Lys Thr Ile Ala Glu Asn
405
<210> 10
<211> 499
<212> PRT
<213> 智人(Homo sapiens)
<220>
<221> 人肝素辅因子 2 (HEP2)
<222> (1)..(499)
<400> 10
Met Lys His Ser Leu Asn Ala Leu Leu Ile Phe Leu Ile Ile Thr Ser
1 5 10 15
Ala Trp Gly Gly Ser Lys Gly Pro Leu Asp Gln Leu Glu Lys Gly Gly
20 25 30
Glu Thr Ala Gln Ser Ala Asp Pro Gln Trp Glu Gln Leu Asn Asn Lys
35 40 45
Asn Leu Ser Met Pro Leu Leu Pro Ala Asp Phe His Lys Glu Asn Thr
50 55 60
Val Thr Asn Asp Trp Ile Pro Glu Gly Glu Glu Asp Asp Asp Tyr Leu
65 70 75 80
Asp Leu Glu Lys Ile Phe Ser Glu Asp Asp Asp Tyr Ile Asp Ile Val
85 90 95
Asp Ser Leu Ser Val Ser Pro Thr Asp Ser Asp Val Ser Ala Gly Asn
100 105 110
Ile Leu Gln Leu Phe His Gly Lys Ser Arg Ile Gln Arg Leu Asn Ile
115 120 125
Leu Asn Ala Lys Phe Ala Phe Asn Leu Tyr Arg Val Leu Lys Asp Gln
130 135 140
Val Asn Thr Phe Asp Asn Ile Phe Ile Ala Pro Val Gly Ile Ser Thr
145 150 155 160
Ala Met Gly Met Ile Ser Leu Gly Leu Lys Gly Glu Thr His Glu Gln
165 170 175
Val His Ser Ile Leu His Phe Lys Asp Phe Val Asn Ala Ser Ser Lys
180 185 190
Tyr Glu Ile Thr Thr Ile His Asn Leu Phe Arg Lys Leu Thr His Arg
195 200 205
Leu Phe Arg Arg Asn Phe Gly Tyr Thr Leu Arg Ser Val Asn Asp Leu
210 215 220
Tyr Ile Gln Lys Gln Phe Pro Ile Leu Leu Asp Phe Lys Thr Lys Val
225 230 235 240
Arg Glu Tyr Tyr Phe Ala Glu Ala Gln Ile Ala Asp Phe Ser Asp Pro
245 250 255
Ala Phe Ile Ser Lys Thr Asn Asn His Ile Met Lys Leu Thr Lys Gly
260 265 270
Leu Ile Lys Asp Ala Leu Glu Asn Ile Asp Pro Ala Thr Gln Met Met
275 280 285
Ile Leu Asn Cys Ile Tyr Phe Lys Gly Ser Trp Val Asn Lys Phe Pro
290 295 300
Val Glu Met Thr His Asn His Asn Phe Arg Leu Asn Glu Arg Glu Val
305 310 315 320
Val Lys Val Ser Met Met Gln Thr Lys Gly Asn Phe Leu Ala Ala Asn
325 330 335
Asp Gln Glu Leu Asp Cys Asp Ile Leu Gln Leu Glu Tyr Val Gly Gly
340 345 350
Ile Ser Met Leu Ile Val Val Pro His Lys Met Ser Gly Met Lys Thr
355 360 365
Leu Glu Ala Gln Leu Thr Pro Arg Val Val Glu Arg Trp Gln Lys Ser
370 375 380
Met Thr Asn Arg Thr Arg Glu Val Leu Leu Pro Lys Phe Lys Leu Glu
385 390 395 400
Lys Asn Tyr Asn Leu Val Glu Ser Leu Lys Leu Met Gly Ile Arg Met
405 410 415
Leu Phe Asp Lys Asn Gly Asn Met Ala Gly Ile Ser Asp Gln Arg Ile
420 425 430
Ala Ile Asp Leu Phe Lys His Gln Gly Thr Ile Thr Val Asn Glu Glu
435 440 445
Gly Thr Gln Ala Thr Thr Val Thr Thr Val Gly Phe Met Pro Leu Ser
450 455 460
Thr Gln Val Arg Phe Thr Val Asp Arg Pro Phe Leu Phe Leu Ile Tyr
465 470 475 480
Glu His Arg Thr Ser Cys Leu Leu Phe Met Gly Arg Val Ala Asn Pro
485 490 495
Ser Arg Ser
Claims (15)
1.用于筛选、诊断和/或监测对象中的亚临床动脉粥样硬化,优选全身性亚临床动脉粥样硬化的方法,其中所述方法包括:
a)测定从所述对象分离的生物样品中的以下蛋白质的表达水平:
i.PIGR和/或IGHA2;以及
ii.任选地,选自APOA、HPT、HEP2、ITIH1和C5的一种、两种、三种、四种或五种生物标志物;
b)将所述生物标志物的水平与参考值进行比较;
c)其中当所述对象的样品中PIGR、IGHA2、APOA、HPT、HEP2、ITIH1和/或C5的水平相对于相应的参考值增加时,表明亚临床动脉粥样硬化。
2.如权利要求1所述的方法,其中步骤a)包括测定PIGR和/或IGHA2以及选自APOA、HPT、HEP2、ITIH1和C5的一种、两种、三种、四种或五种生物标志物的蛋白表达水平。
3.如权利要求1或2中任一项所述的方法,其中步骤a)包括测定选自以下的多种生物标志物的蛋白表达水平:
a.PIGR和/或IGHA2和APOA;
b.PIGR和/或IGHA2和HPT;
c.PIGR和/或IGHA2和HEP2;
d.PIGR和/或IGHA2和C5;
e.PIGR和/或IGHA2和ITIH1;
f.PIGR和/或IGHA2、APOA和HPT;
g.PIGR和/或IGHA2、APOA和HEP2;
h.PIGR和/或IGHA2、APOA和C5;
i.PIGR和/或IGHA2、APOA和ITIH1;
j.PIGR和/或IGHA2、HPT和HEP2;
k.PIGR和/或IGHA2、HPT和C5;
l.PIGR和/或IGHA2、HPT和ITIH1;
m.PIGR和/或IGHA2、HEP2和C5;
n.PIGR和/或IGHA2、HEP2和ITIH1;
o.PIGR和/或IGHA2、APOA、HPT和C5;
p.PIGR和/或IGHA2、APOA、HPT和ITIH1;
q.PIGR和/或IGHA2、APOA、HEP2和C5;
r.PIGR和/或IGHA2、APOA、HEP2和ITIH1;
s.PIGR和/或IGHA2、HPT、HEP2和C5;
t.PIGR和/或IGHA2、HPT、HEP2和ITIH1;以及
u.PIGR和/或IGHA2、APOA、HPT和HEP2。
4.如权利要求1至3中任一项所述的方法,其中所述方法还包括测定所述生物样品中IGHG1的蛋白表达水平;其中当所述对象的样品中的IGHG1水平相对于参考值降低时,表明亚临床动脉粥样硬化。
5.如权利要求1至3中任一项所述的方法,其中IGHA2水平是相对于IGHA1、IGHG1、IGHG2中任一种或其组合的相对水平,优选地其中IGHA2水平是相对于IGHA1或相对于IGHG1和IGHG2的平均水平的相对水平。
6.如权利要求1至5中任一项所述的方法,其中所述方法还包括进行传统的心血管风险评分,优选地其中所述传统的心血管风险评分选自10-y FHS、30-y FHS、ICHS和BEWAT评分,更优选地其中所述心血管风险评分是10-y FHS。
7.如权利要求1至6中任一项所述的方法,其中所述方法是用于在进行传统的心血管风险评分时被分类为低风险的对象中进行筛选和/或诊断亚临床动脉粥样硬化的方法。
8.如权利要求1至7中任一项所述的方法,其中从所述对象分离的所述生物样品是血清、血液或血浆样品,优选血清样品。
9.如权利要求1至8中任一项所述的方法,其中所述对象是人类对象。
10.如权利要求1至9中任一项所述的方法,其中步骤b)和/或c)由计算机实现。
11.数据处理设备,其包括用于执行权利要求10所述的方法中的步骤的装置。
12.计算机程序,其包括指令,当所述程序由计算机执行时,所述指令使所述计算机执行权利要求10所述的方法中的步骤。
13.计算机可读存储介质,其上存储有权利要求12所述的计算机程序。
14.试剂盒,其包含足以测定以下生物标志物的蛋白质表达水平的试剂:
i.PIGR和/或IGHA2;
ii.任选地,选自APOA、HPT、HEP2、ITIH1和C5的一种、两种、三种、四种或五种生物标志物;
其中所述试剂盒包含:
a.针对PIGR和/或IGHA2的亲和试剂;
b.任选地,针对APOA、HPT、HEP2、ITIH1和C5中的一种、两种、三种、四种或五种的亲和试剂;
c.任选地,还包含使用所述试剂测定从对象分离的生物样品中所述蛋白质表达水平的说明书。
15.试剂盒在用于权利要求1至10中任一项所述的对象的筛选、诊断和/或监测的方法中的用途,其中所述试剂盒包含:
a.用于测定PIGR和/或IGHA2的蛋白表达水平的试剂;以及
b.任选地,用于测定APOA、HPT、HEP2、ITIH1或C5中的一种、两种、三种、四种或五种的蛋白表达水平的试剂;
c.任选地,还包含使用所述试剂测定从对象分离的生物样品中所述蛋白表达水平的说明书;
优选地,其中所述试剂盒如权利要求14中所定义。
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