CN103981280B - 用于预测患2型糖尿病肾病发生风险的标记物及其用途 - Google Patents
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Abstract
本发明涉及一种用于预测患2型糖尿病肾病发生风险的标记物，该述标记物为人类基因组编号为rs3733570的SNP位点的基因型，该SNP位点的基因型的存在标志着患有2型糖尿病肾病的发生风险,其可提高2型糖尿病肾病预测的准确性，对2型糖尿病肾病的早期预测发病风险，便于高危人群通过及早治疗及改变生活方式来减少2型糖尿病肾病的发生。
Description
技术领域
本发明涉及分子生物学和医学领域，特别涉及一种用于预测患2型糖尿病肾病发生风险的标记物及其用途。
背景技术
糖尿病是一种糖、蛋白质、脂肪代谢障碍的慢性综合征，继发于胰岛素分泌不足，或靶组织产生抗胰岛素性；有两种主要型：胰岛素依赖性糖尿病(1型)和非胰岛素依赖性糖尿病(2型)。
2型糖尿病(type2diabetesmellitus，T2DM)的发病受到环境和基因双重因素的影响。遗传因素能增加机体发生2型糖尿病的危险性。目前T2DM的发病率在所有种族和年龄段均逐渐上升。虽然进行了大量的基因组关联分析，但是大部分T2DM相关基因仍然未知。
2型糖尿病肾病(diabetic nephropathy，DN)是T2DM的一个常见并发症，其发展也受到环境和基因双重因素的影响；DN能导致T2DM患者终末期肾病；是成人慢性肾功能衰竭病首要原因；也是糖尿病患者发病和致死的主要原因。所以当务之急是研究DN的易感基因，以此来预测2型糖尿病肾病的发生风险及开展针对此基因的药物治疗；目前一些基因组扫描(genome-wide scans，GWS)和相关性研究已经发现一些基因与DN密切相关，但是DN发生的所有易感基因并未完全明确。因此为了研究2型糖尿病肾病及其发病机制，预测患2型糖尿病肾病的发生风险，需要生物学家及医学家更多的发现2型糖尿病肾病的相关基因。
发明内容
为了解决上述技术问题，本发明提供一个新的能预测患2型糖尿病肾病发生风险的标记物。
本发明具体技术方案如下：
本发明提供一种用于预测人患2型糖尿病肾病发生风险的标记物，该述标记物为人类基因组编号为rs3733570的SNP(single nucleotidepolymorphism)位点的基因型，该SNP位点的基因型的存在标志着患2型糖尿病肾病的发生风险。
rs3733570的相关信息可从http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi？rs＝3733570中找到依据。
进一步的改进，所述SNP位点的基因型为rs3733570的基因型。
进一步的改进，所述rs3733570的T等位基因的存在标志着患2型糖尿病肾病的发生风险增高。
进一步的改进，所述rs3733570的T/T基因型的存在标志着患2型糖尿病肾病的发生风险增高。
进一步的改进，所述rs3733570的共显性中C/T和T/T基因型的存在，或显性中C/T和T/T基因型的存在，或隐性中T/T基因型的存在标志着患2型糖尿病肾病的发生风险增高。
进一步的改进，所述共显性中T/T基因型患2型糖尿病肾病的发生风险是C/C基因型的7-8倍；C/T基因型患2型糖尿病肾病的发生风险是C/C基因型的3-4倍；显性中C/T和T/T基因型患2型糖尿病肾病的发生风险是C/C基因型的4-5倍；隐性中T/T基因型患2型糖尿病肾病的发生风险是C/C和C/T基因型的3-4倍。
进一步的改进，所述标记物在用作预测患2型糖尿病肾病发生风险的试剂中的应用。
本发明所述2型糖尿病肾病患者为亚洲人。
本发明另一方面提供了识别标记物的方法，该标记物的存在标志着患2型糖尿病肾病的发生风险，该方法包括如下步骤：
a.收取EDTA-K2抗凝静脉全血；
b.通过全血PCR扩增体系扩增rs3733570所在外显子片段；
c.将b步骤获得的PCR产物纯化；
d.将步骤c得到的纯化产物，经测序仪(3730xl，ABI)测序；
e.分析结果。
进一步的改进，所述扩增步骤包括：94℃3分钟，55℃3分钟循环4次；94℃变性5分钟后进入循环，94℃变性30秒，52℃退火30秒，72℃延伸90秒，40个周期后，72℃延伸5分钟，4℃保持。
本发明进一步还提供了利用上述标记物预测患2型糖尿病肾病发生风险的方法，该方法包括如下步骤：
a)收取EDTA-K2抗凝静脉全血；
b)检测全血中rs3733570SNP位点的基因型；
c)所述rs3733570共显性中，T/T基因型会使患者发展为2型糖尿病肾病的风险与正常患者相比增加7-8倍。
本发明的有益效果，本发明提供一种用于预测患2型糖尿病肾病发生风险的标记物，该标记物为人类基因组编号为rs3733570的SNP位点的基因型，其可提高2型糖尿病肾病预测的准确性，对2型糖尿病肾病的早期预测发病风险，便于高危人群通过及早治疗及改变生活方式来减少2型糖尿病肾病的发生。
具体实施方式
实施例1
一种标记物，该标记物为人类基因组编号为rs3733570的SNP位点的基因型，所述SNP位点的基因型为rs3733570的基因型，其中，rs3733570共显性中T/T基因型患2型糖尿病肾病的发生风险是C/C基因型的7.69倍；
所述标记物的识别方法为：
a.收取EDTA-K2抗凝静脉全血；
b.通过全血PCR扩增体系扩增rs3733570所在外显子片段；扩增步骤为：94℃3分钟，55℃3分钟循环4次；94℃变性5分钟后进入循环，94℃变性30秒，52℃退火30秒，72℃延伸90秒，40个周期后，72℃延伸5分钟，4℃保持；
c.将b步骤获得的PCR产物纯化；
d.将步骤c得到的纯化产物，经测序仪(3730xl，ABI)测序；
e.分析结果。
利用所述标记物预测患2型糖尿病肾病发生风险的方法，该方法包括如下步骤：
a)收取EDTA-K2抗凝静脉全血；
b)检测全血中rs3733570SNP位点的基因型；
c)所述rs3733570共显性中，T/T基因型会使患者发展为2型糖尿病肾病的风险与正常患者相比增加7.69倍。
试验例1
1.研究对象
所选取的研究对象为河北省唐山市开滦医院入院病人；研究对象分为高龄未患糖尿病对照组(NC)，2型糖尿病组(T2DM)，2型糖尿病肾病组(DN)三组，NC入组标准为：年龄≥60岁，血糖水平正常(空腹血糖＜6.1mmol/L而且餐后2小时血糖＜7.8mmol/L)，无既往糖尿病史；T2DM标准为符合1999年WHO糖尿病诊断标准并排除具有T1DM及年轻的成人起病糖尿病(MODY)等特殊类型糖尿病；另外需无糖尿病肾病的病史，尿常规蛋白阴性，血肌酐水平正常；DN入组标准为除前述糖尿病的诊断标准外应同时具备，眼科诊断的糖尿病性视网膜病变，尿蛋白阳性(至少2次尿常规蛋白阳性(+～3+)或24小时尿蛋白定量≥0.5g)；无血尿：尿常规红细胞＜3个/高倍视野；各组入组患者必须同时排除：①临床诊断的除糖尿病性肾病以往的其他原发性或继发性肾脏疾病；②血液系统疾病；③恶性肿瘤；本研究的注册号：ChiCTR-TNRC-11001489；伦理委员会批件文号为2006医伦字5号。
2.检测方法：
rs3733570位点所在DNA的扩增
所用试剂2×ES Taq MasterMix(康为世纪，CW0690)
所用引物
sense TTGCCAGTGTATAGGTAAGG
antisense ATTCATTCCAGTGTAGA
所有入组病人留取2ml EDTA-K2抗凝静脉全血分装后保存于-80℃。以全血为DNA模板，PCR扩增rs3733570所在的外显子。按如下程序进行：在94℃3分钟，55℃3分钟循环4次以破坏细胞膜及核膜释放基因组DNA；94℃变性5分钟后进入循环，94℃变性30秒，52℃退火30秒，72℃延伸90秒，40个周期后72℃延伸5分钟，4℃保持；PCR产物经纯化后经测序仪(3730xl，ABI)分析后获得序列；获得的序列观察rs3733570为何种核苷酸；
3.统计学分析方法
描述性统计资料年龄用方差分析，性别用卡方检验；基因型分布温-哈平衡(Hardy-Weinberg equilibrium，HWE)用HW计算器；运用非条件logistic回归计算相对危险度(odds ratio，OR)和95％可信区间(95％confidence interval，95％CI)，p<0.05被认为有统计学差异。
4.结果
研究对象的临床特征见表1；
rs3733570在人群中的分布见表2；
rs3733570与2型糖尿病肾病的相关性见表3；
表一研究对象的临床特征
Pa未患糖尿病对照组与各组相比。
从表1可看出，T2DM和DN组与正常人相比年龄有统计学差异(p<0.001)，T2DM和DN组相比年龄无统计学差异，三组性别无统计学差异(p>0.05)。
表二rs3733570在人群中的分布
从表2中可看出，三组基因分布符合HWE模型，结果可靠。
表三rs3733570与2型糖尿病肾病的相关性
a未患糖尿病对照组与2型糖尿病肾病组相比。
从表3中可看出，
在共显性模型中T/T基因型患2型糖尿病肾病的发生风险是C/C基因型的7.69倍；C/T基因型患2型糖尿病肾病的发生风险是C/C基因型的3.67倍；
在显性模型中C/T和T/T基因型患2型糖尿病肾病的发生风险是C/C基因型的4.47倍；
在隐性模型中T/T基因型患2型糖尿病肾病的发生风险是C/C和C/T基因型的3.08倍。
5.结论
由以上表中可以看出，SNP位点rs3733570与糖尿病和糖尿病肾病均具有相关性，并且rs3733570与2型糖尿病肾病相关具有统计学意义。
Claims (7)
1.一种检测标记物的物质用作制备预测2型糖尿病肾病发生风险试剂的应用，其特征在于，所述标记物为人类基因组编号为rs3733570的SNP位点的基因型，所述SNP位点的基因型的存在标志着患2型糖尿病肾病的发生风险。
2.如权利要求1所述的应用，其特征在于，所述SNP位点的基因型为rs3733570的基因型。
3.如权利要求1所述的应用，其特征在于，所述rs3733570的T等位基因的存在标志着患2型糖尿病肾病的发生风险增高。
4.如权利要求3所述的应用，其特征在于，所述rs3733570的T/T基因型的存在标志着患2型糖尿病肾病的发生风险增高。
5.如权利要求4所述的应用，其特征在于，所述rs3733570的共显性中C/T和T/T基因型的存在，或显性中C/T和T/T基因型的存在，或隐性中T/T基因型的存在标志着患2型糖尿病肾病的发生风险增高。
6.如权利要求5所述的应用，其特征在于，所述共显性中T/T基因型患2型糖尿病肾病的发生风险是C/C基因型的7-8倍；C/T基因型患2型糖尿病肾病的发生风险是C/C基因型的3-4倍；显性中C/T和T/T基因型患2型糖尿病肾病的发生风险是C/C基因型的4-5倍；隐性中T/T基因型患2型糖尿病肾病的发生风险是C/C和C/T基因型的3-4倍。
7.如权利要求1-6任一所述的应用，其特征在于，所述2型糖尿病肾病患者为亚洲人。
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