CN110331195A - 一种系统性红斑狼疮骨桥蛋白基因标志物及其筛选方法 - Google Patents
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Abstract
本发明公开了一种系统性红斑狼疮骨桥蛋白基因标志物,该标志物为由骨桥蛋白基因rs1126772,rs11728697,rs4754构建的单体型A‑T‑C,其可用于系统性红斑狼疮检测,并通过以下步骤筛选得到:(a)受试者人群的选取;(b)基因组DNA的提取;(c)基因组DNA的PCR扩增;(d)扩增后的基因组DNA测序、对照;(e)得到骨桥蛋白基因标志物。提供了一种用于系统性红斑狼疮精确诊断的骨桥蛋白基因标志物及该标志物的筛选方法,提高了医学精确诊断水平。
Description
技术领域
本发明涉及医学检测技术领域,具体涉及一种系统性红斑狼疮骨桥蛋白基因标志物及其筛选方法。
背景技术
系统性红斑狼疮(SLE)是一种自身免疫性炎症结缔组织疾病,涉及全身多个组织器官,包括皮肤、黏膜、关节、心脏、肾脏等,临床表现形式多样。遗传、内分泌、感染、免疫异常和一些环境因素被认为是SLE的发病机制,大多数学者认为遗传因素起着关键作用。
然而系统性红斑狼疮的检测在目前临床医学中仍然是一个难题,缺乏有效的基因标志物以完成系统性红斑狼疮的精确诊断及得到该基因标志物的筛选方法。
发明内容
本发明为了解决上述问题,提供了一种系统性红斑狼疮骨桥蛋白基因标志物,该标志物为由骨桥蛋白基因rs1126772,rs11728697, rs4754构建的单体型A-T-C,其可用于系统性红斑狼疮检测并通过以下步骤筛选得到:
(a)受试者人群的选取;
(b)基因组DNA的提取;
(c)基因组DNA的PCR扩增;
(d)扩增后的基因组DNA测序、对照;
(e)得到骨桥蛋白基因标志物。
进一步的,所述受试者人群分为正常组和患病组,正常组和患病组样本大小为200。
进一步的,所述基因组DNA的PCR扩增选用引物为:
rs1126772,正向引物序列为:5′-GCAAAATGAAAGAGAACAT GAAATGC-3′;反向引物序列为:5′-CTGGACAACCGTGGGAAAAC AA-3′;延伸引物序列为:5′-TTTTTTTACAAACTAAACTAATTATCA AACACAT-3′;
rs11728697,正向引物序列为:5′-CAAGCTACTGCATACTCGA AATCACAA-3′;反向引物序列为:5′-GGGATCCCATGAAAAAGGG AGA-3′;延伸引物序列为:5′-TTTTTTTTTTTTTTTTTTTTTTTTTTT TTTTTTTTTTTTTTTTAAGCCTGCAAGGAGTTCAGA-3′
rs4754,正向引物序列为:5′-TTCCCGGCCATCTTAATTTTCA-3 ′;反向引物序列为:5′-AAAACTTCGGTTGCTGGCAGGT-3′;延伸引物序列为:5′-TTTTTTTTTTTTTTGAGTCCTGGCTGTCCACATGG TC-3′。
本发明的有益效果:提供了一种用于系统性红斑狼疮精确诊断的骨桥蛋白基因标志物及该标志物的筛选方法,提高了医学精确诊断水平。
具体实施方式
下面对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。
一种系统性红斑狼疮骨桥蛋白基因标志物,该标志物为由骨桥蛋白基因rs1126772,rs11728697,rs4754构建的单体型A-T-C,其可用于系统性红斑狼疮检测,并通过以下步骤筛选得到:
(a)受试者人群的选取;
(b)基因组DNA的提取;
(c)基因组DNA的PCR扩增;
(d)扩增后的基因组DNA测序、对照;
(e)得到骨桥蛋白基因标志物。
其中的,所述受试者人群分为正常组和患病组,正常组和患病组样本大小为200。
其中的,所述基因组DNA的PCR扩增选用引物为:
rs1126772,正向引物序列为:5′-GCAAAATGAAAGAGAACAT GAAATGC-3′;反向引物序列为:5′-CTGGACAACCGTGGGAAAAC AA-3′;延伸引物序列为:5′-TTTTTTTACAAACTAAACTAATTATCA AACACAT-3′;
rs11728697,正向引物序列为:5′-CAAGCTACTGCATACTCGA AATCACAA-3′;反向引物序列为:5′-GGGATCCCATGAAAAAGGG AGA-3′;延伸引物序列为:5′-TTTTTTTTTTTTTTTTTTTTTTTTTTT TTTTTTTTTTTTTTTTAAGCCTGCAAGGAGTTCAGA-3′
rs4754,正向引物序列为:5′-TTCCCGGCCATCTTAATTTTCA-3 ′;反向引物序列为:5′-AAAACTTCGGTTGCTGGCAGGT-3′;延伸引物序列为:5′-TTTTTTTTTTTTTTGAGTCCTGGCTGTCCACATGG TC-3′。
本实施例通过以下实验进行验证本发明的效果:
1.材料和方法
1.1研究对象根据1997年美国风湿病学会(ACR)关于SLE的诊断标准,选择右江民族医学院附属医院经临床诊断为SLE的200名女性患者作为病例组,排除恶性肿瘤、传染病和其他自身免疫性疾病。同时,选择同一时期就诊的200名年龄匹配的健康女性作为对照组。所有研究对象均为居住于百色市的中国居民。本研究通过右江民族医学院附属医院伦理委员会批准,并获得所有研究对象的书面知情同意。
1.2OPN SNPs的选择在PubMed中选择合适的OPN SNPs具体标准如下:(a)在汉族HapMap数据库中选择最小等位基因频率(MAF)大于0.05的SNP;(b) 优先选择启动子区、外显子区、5‘-UTR区、3’-UTR区的SNP;(c) 参阅关于OPN SNPs和其他疾病的相关文献。
1.3DNA提取与OPN基因分型利用全血基因组DNA提取试剂盒[亚能生物技术(深圳)有限公司(中国深圳)]从外周血中提取基因组DNA。PCR引物根据GenBank中的参考序列用在线软件Primer3(http://frodo.wi.mit.edu/cgi-bin/primer3/pr imer3_www.cgi)设计(见表1)。采用多核苷酸引物延伸技术检测OP N SNPs(rs 1126772,rs 11728697,rs 4754)的基因型,应用生物系统技术(Genemapper4.1)对基因分型结果进行分析。采用SNaPshot多重单碱基延伸反应检测OPN SNPs(rs 1126772,rs 11728697,rs 475 4)的基因型并应用GeneMapper4.1(Appliedbiosystems)来分析基因分型结果。
表1.引物序列表
1.4统计分析
研究对象与Hardy-Weinbery平衡的符合程度采用χ2检验,用卡方检验分析3个SNPs基因型和等位基因频率在病例组与对照组之间的差异。OPN多态性与SLE风险之间的相关性程度用95%置信区间 (95%CI)的优势比(OR)表示。OR,95%CI和P值根据年龄用logistic回归进行校正。用R2评价连锁不平衡强度,用SHEsis(http://analysis.bio- x.cn/myAnalysis.php)在线软件进行单倍型分析。所有数据均采用SPSS17.0软件包进行分析。
2.结果
2.1研究对象的临床特征及实验室参数
SLE患者和对照组的临床特征和实验室参数见表2。病例组与对照组年龄的差异无显著性(P=0.088)。
表2SLE患者和对照组的临床特征及实验室参数
2.2OPN基因多态性与SLE的关系
SLE组和对照组OPN基因rs 1126772、rs 11728697、rs 4754 位点的基因型和等位基因频率见表3。两组的基因型分布均符合Har dy-Weinbery遗传平衡定律(HWE)(P>0.05)。rs11728697的CT和CT +TT基因型与SLE的易感性相关(CT vs.CC:校正OR=1.713,9 5%CI,1.122-2.672,P=0.013;CT+TT vs.CC:校正OR=1.549,9 5%CI,1.010-1.041,P=0.036)。然而,rs1126772和rs4754与SLE的易感性无关(P>0.05)。
表3SLE组和对照组OPN基因的基因型和等位基因频率
注:a,按年龄校正,Ref,参照组。
2.3OPN基因的单倍型分析
单倍型由SHEsis在线软件分析,可能的单倍型频率如表4所示。 rs 1126772分别与rs 11728697和rs 4754处于强连锁不平衡状态。主要的单倍型(A-C-C)在SLE和对照组中分别占41.2%和45.7%,单倍型A-T-C与SLE的风险增加有关(OR=1.771,95%CI,1.005-3.118, P=0.045)。
表4单倍型在SLE组及对照组中的分布
2.4 rs 11728697多态性与SLE临床特征及实验室参数的关系
为了进一步探讨rs 11728697与SLE易感性的关系,我们比较了 7种特异性临床表现和16项实验室指标(8种特异性抗体、6种免疫因子和2种炎症标志物)阳性组和阴性组的rs 11728697基因型和等位基因频率。在临床表现中,我们发现rs 11728697CT+TT基因型对光敏性有保护作用,而T等位基因则与SLE肾功能紊乱的风险增加有关(CT+TT vs.CC:OR=0.338,95%CI,1.182-0.629,P=0.000;T vs.C: OR=1.673,95%CI,1.113-2.514,P=0.013)。在实验室参数上, rs11728697CT+TT基因型在抗Sm阳性和阴性患者之间的分布有显着性差异(CT+TT vs.CC:OR=2.016,95%CI,1.114-3.648,P=0.020)。此外,我们还发现rs11728697CT+TT基因型在IgG水平升高的患者和未升高的患者之间的分布有差异(CT+TTvs.CC:OR=1.954, 95%CI,1.065-3.581,P=0.029)(表5)。
表5 rs 11728697基因型和等位基因频率与SLE临床特征及实验室参数的关系
在本说明书的描述中,参考术语“一个实施例”、“示例”、“具体示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不一定指的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
以上公开的本发明优选实施例只是用于帮助阐述本发明。优选实施例并没有详尽叙述所有的细节,也不限制该发明仅为所述的具体实施方式。显然,根据本说明书的内容,可作很多的修改和变化。本说明书选取并具体描述这些实施例,是为了更好地解释本发明的原理和实际应用,从而使所属技术领域技术人员能很好地理解和利用本发明。本发明仅受权利要求书及其全部范围和等效物的限制。
Claims (5)
1.一种系统性红斑狼疮骨桥蛋白基因标志物,其特征在于,由骨桥蛋白基因rs1126772,rs11728697,rs4754构建的单体型A-T-C。
2.根据权利要求1所述的标志物用于系统性红斑狼疮检测。
3.用于权利要求1所述的标志物的筛选方法,其特征在于,包括以下步骤:
(a)受试者人群的选取;
(b)基因组DNA的提取;
(c)基因组DNA的PCR扩增;
(d)扩增后的基因组DNA测序、对照;
(e)得到骨桥蛋白基因标志物。
4.根据权利要求3所述的方法,其特征在于,所述受试者人群分为正常组和患病组,正常组和患病组样本大小为200。
5.根据权利要求3所述的方法,其特征在于,所述基因组DNA的PCR扩增选用引物为:
rs1126772,正向引物序列为:5′-GCAAAATGAAAGAGAACATGAAATGC-3′;反向引物序列为:5′-CTGGACAACCGTGGGAAAACAA-3′;延伸引物序列为:5′-TTTTTTTACAAACTAAACTAATTATCAAACACAT-3′;
rs11728697,正向引物序列为:5′-CAAGCTACTGCATACTCGAAATCACAA-3′;反向引物序列为:5′-GGGATCCCATGAAAAAGGGAGA-3′;延伸引物序列为:5′-TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTAAGCCTGCAAGGAGTTCAGA-3′
rs4754,正向引物序列为:5′-TTCCCGGCCATCTTAATTTTCA-3′;反向引物序列为:5′-AAAACTTCGGTTGCTGGCAGGT-3′;延伸引物序列为:5′-TTTTTTTTTTTTTTGAGTCCTGGCTGTCCACATGGTC-3′。
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