血浆长链非编码RNA RNF5P1作为缺血性脑卒中生物标记物的研究

温莹; 汤月芳; 黄素丽; 张艳炜; 周丽; 李頔; 柯跃斌; 程锦泉; 陈青山

doi:10.16462/j.cnki.zhjbkz.2020.06.016

血浆长链非编码RNA RNF5P1作为缺血性脑卒中生物标记物的研究

doi: 10.16462/j.cnki.zhjbkz.2020.06.016

温莹¹,
汤月芳²,
黄素丽³,
张艳炜⁴,
周丽⁵,
李頔⁵,
柯跃斌¹,
程锦泉¹,
陈青山^2, ,

1.
518055 深圳, 深圳市疾病预防控制中心分子流行病研究室
2.
510632 广州, 暨南大学医学院公共卫生与预防医学系
3.
518055 深圳, 深圳市疾病预防控制中心环境与健康所
4.
518055 深圳, 深圳市疾病预防控制中心免疫规划所
5.
518055 深圳, 深圳市疾病预防控制中心学校卫生所

温莹和汤月芳为共同第一作者

基金项目: 国家自然科学基金面上项目(81573242);国家自然科学基金青年基金项目(81703312);深圳市科技计划项目(JCYJ20170306160036900)

详细信息

通讯作者:
陈青山, E-mail:data88@126.com

中图分类号: R181
计量
- 文章访问数: 265
- HTML全文浏览量: 166
- PDF下载量: 27
- 被引次数: 0
出版历程
- 收稿日期: 2019-10-30
- 修回日期: 2020-02-18
- 刊出日期: 2020-06-10

Study on plasma lncRNA RNF5P1 as a biomarker for ischemic stroke

1.
Department of Molecular Epidemiology, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China
2.
Department of Public Health and Preventive Medicine, Jinan University School of Medicine, Guangzhou 510632, China
3.
Department of Environment and Health, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China
4.
Department of Immunization Planning and Management, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China
5.
Department of School Health, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China

WEN Ying and TANG Yue-fang are contributed equally to this article

Funds: General Program of National Natural Science Foundation of China(81573242);Youth Program of National Natural Science Foundation of China(81703312); Shenzhen Science and Technology Project(JCYJ20170306160036900)

More Information

Corresponding author: CHEN Qing-shan, E-mail:data88@126.com

摘要

摘要: 目的探讨血浆长链非编码RNA(lncRNA)RNF5P1表达水平与缺血性脑卒中(ischemic stroke, IS)发病风险的关联, 评估血浆RNF5P1作为IS生物标记物的可行性。方法采用1:1匹配的病例对照研究, 在深圳地区选取302对性别年龄匹配的IS新发病例和正常体检对照, 采用微滴式数字PCR检测血浆lncRNA RNF5P1的表达水平, 采用条件Logistic回归分析模型分析RNF5P1表达水平与IS发病风险之间的关联, 采用受试者工作特征曲线及重新分类的方法评估RNF5P1是否可作为IS的分子标记物。结果 IS病例组血浆lncRNA RNF5P1的表达水平高于对照组, 差异有统计学意义(P < 0.001)。高表达水平的RNF5P1与IS发病风险增加有关, 校正其他危险因素后, OR值为2.52(95% CI:1.12~5.64)。与传统危险因素模型相比, 加入lncRNA RNF5P1后, 模型的曲线下面积增加(P < 0.001), 净重分类改善度为0.42(95% CI:0.26~0.57), 综合区分改善度为0.24(95% CI:0.14~0.34)。结论血浆lncRNA RNF5P1表达水平升高与IS发病风险增加有关, lncRNA RNF5P1有望作为IS的生物标记物。
- 缺血性脑卒中 /
- 长链非编码RNA /
- 血浆 /
- 生物标记物
Abstract: Objective To explore the association between the expression level of plasma long non-coding RNA(lncRNA) RNF5 P1 and the risk of ischemic stroke(IS), and to examine the potential of RNF5 P1 as a biomarker for IS. Methods A 1:1 matched case-control study with 302 pairs of newly diagnosed IS patients and controls was conducted in Shenzhen. LncRNA expression levels were measured using droplet digital polymerase chain reaction. Conditional logistic regression model was used to assess the association between plasma RNF5 P1 expression level and IS risk. The receiver operating characteristic(ROC) and reclassification analysis were conducted to assess the feasibility of using plasma RNF5 P1 as a novel biomarker for the detection of IS. Results The expression levels of lncRNA RNF5 P1 were signific-antly higher in the patients with IS than the controls(P < 0.001). The higher expression level of RNF5 P1 was associated with increased risk of IS, and the adjusted odds ratio was 2.52(95%CI: 1.12-5.64). Addition of RNF5 P1 to the well-recognized risk factors led to significant improvement in the area under the ROC curve(P < 0.001), with a net reclassification improvement of 0.42(95%CI:0.26-0.57) and an integrated discrimination improvement of 0.24(95% CI: 0.14-0.34). Conclusions The level of plasma RNF5 P1 is positively associated with the risk of IS. Our results suggest the potential for plasma lncRNA RNF5 P1 to be used as a novel molecular biomarker for IS.
- Ischemic stroke /
- Long non-coding RNA /
- Plasma /
- Biomarker

HTML全文

图 1 LncRNA RNF5P1在对照与病例人群血浆中的表达情况

Figure 1. Expression levels of plasma lncRNA RNF5P1 in controls and IS cases

下载: 全尺寸图片幻灯片

图 2 血浆lncRNA RNF5P1的ROC曲线分析

Figure 2. ROC analysis of plasma lncRNA RNF5P1 as the diagnostic biomarker for IS

下载: 全尺寸图片幻灯片

表 1 两组人群基本情况比较[n(%)]

Table 1. Basic characteristics of the study population [n(%)]

变量	病例组(n=302)	对照组(n=302)	t/χ²/Z值	P值
年龄(岁, x±s)	63.28±8.85	63.30±8.45	0.410	0.682
男性	184(60.93)	184(60.93)	0.000	1.000
BMI(kg/m², x±s)	24.01±3.19	23.63±2.88	-1.601	0.110
吸烟	44(14.57)	52(17.22)	0.645	0.422
饮酒	13(4.30)	40(13.25)	13.796	< 0.001
高血压	225(74.50)	130(43.05)	54.882	< 0.001
糖尿病	108(35.76)	46(15.23)	31.534	< 0.001
高脂血症	90(29.80)	100(33.11)	0.623	0.430
CRP[mg/dl, M(P₂₅, P₇₅)]	2.34(1.07, 5.90)	0.17(0.12, 0.27)	-5.763	< 0.001

下载: 导出CSV

表 2 血浆lncRNA RNF5P1表达水平与IS发病风险的关联性

Table 2. Association between the plasma lncRNA RNF5P1 expression level and the IS risk

RNF5P1	n(对照/病例)	模型1^a		模型2^b
RNF5P1	n(对照/病例)	OR (95% CI)值	P值	OR (95% CI)值	P值
低表达(< -5.11)	151/57	1.00		1.00
高表达(≥-5.11)	151/245	5.27(3.34~8.32)	< 0.001	2.52(1.12~5.64)	0.025
连续模型	-	3.37(2.46~4.63)	< 0.001	1.91(1.16~3.17)	0.012
注:^a单因素条件Logistic回归模型; ^b多因素条件Logistic回归模型, 在纳入RNF5P1的基础上同时调整BMI、吸烟、饮酒、高血压、糖尿病、高脂血症及CRP水平。

下载: 导出CSV

表 3 血浆lncRNA RNF5P1的曲线下面积、净重分类改善度和综合区分改善度

Table 3. Reclassification analysis of plasma lncRNA RNF5P1 as the diagnostic biomarker for IS

模型	AUC (95% CI)	P值^d	NRI (95% CI)值	IDI (95% CI)值
模型1^a	0.74(0.70~0.77)	-	-	-
模型2^b	0.71(0.67~0.74)	-	-	-
模型3^c	0.79(0.76~0.82)	< 0.001	0.42(0.26~0.57)	0.24(0.14~0.34)
注:^a包括性别、年龄、BMI、吸烟、饮酒、高血压、糖尿病及高脂血症等传统危险因素; ^b包括RNF5P1;^c在模型1的基础上纳入了RNF5P1;^d表示模型3的AUC与模型1相比, 是否存在差异。

下载: 导出CSV

参考文献(17)

[1]	Liu L, Wang D, Wong KS, et al. Stroke and stroke care in China: huge burden, significant workload, and a national priority[J]. Stroke, 2011, 42(12): 3651-3654.DOI: 10. 1161/STROKEAHA. 111. 635755.
[2]	国家卫生和计划生育委员会.中国卫生和计划生育统计年鉴2016[M].北京: 中国协和医科大学出版社, 2016. National Health and Family Planning Commission. China health and family planning statistical yearbook 2016[M]. Beijing: China Union Medical University Press, 2016.
[3]	Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions[J]. Nat Rev Genet, 2009, 10(3): 155-159.DOI: 10. 1038/nrg2521.
[4]	Uchida S, Dimmeler S. Long noncoding RNAs in cardiovascular diseases[J]. Circ Res, 2015, 116(4): 737-750.DOI: 10. 1161/CIRCRESAHA. 116. 302521.
[5]	Leung A, Stapleton K, Natarajan R. Functional long non-coding RNAs in vascular smooth muscle cells[J]. Curr Top Microbiol Immunol, 2016, 394: 127-141.DOI: 10. 1007/82_2015_441.
[6]	袁冬妹, 吴思英, 黄素丽, 等.血浆miRNA表达与儿童急性淋巴细胞白血病风险的关联研究[J].中华流行病学杂志, 2017, 38(9): 1252-1258.DOI: 10. 3760/cma. j. issn. 0254-6450. 2017. 09. 022. Yuan DM, Wu SY, Huang SL, et al. Association between expression of plasma miRNA and the risk of childhood acute lymphocytic leukemia[J]. Chin J Epidemiol, 2017, 38(9): 1252-1258. DOI: 10. 3760/cma. j. issn. 0254-6450. 2017. 09. 022.
[7]	Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association[J]. Stroke, 2013, 44(3): 870-947.DOI: 10. 1161/STR. 0b013e318284056a.
[8]	Chalela JA, Kidwell CS, Nentwich LM, et al. Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison[J]. Lancet, 2007, 369(9558): 293-298.DOI: 10. 1016/S0140-6736(07)60151-2.
[9]	王伊龙, 王拥军, 吴敌, 等.中国卒中防治研究现状[J].中国卒中杂志, 2007, 2(1): 20-37.DOI: 10. 3969/j. issn. 1673-5765. 2007. 01. 007. Wang YL, Wang YJ, Wu D, et al. Current situation of stroke prevention and treatment in China[J]. Chin J Stroke, 2007, 2(1): 20-37. DOI: 10. 3969/j. issn. 1673-5765. 2007. 01. 007.
[10]	Granger CB, Laskowitz DT. Biomarkers in stroke: when will they impact care[J]. J Am Coll Cardiol, 2010, 56(13): 1054-1055.DOI: 10. 1016/j. jacc. 2010. 05. 033.
[11]	Wilusz JE, Sunwoo H, Spector DL. Long noncoding RNAs: functional surprises from the RNA world[J]. Genes Dev, 2009, 23(13): 1494-1504.DOI: 10. 1101/gad. 1800909.
[12]	Zhang J, Yuan L, Zhang X, et al. Altered long non-coding RNA transcriptomic profiles in brain microvascular endothelium after cerebral ischemia[J]. Exp Neurol, 2016, 277: 162-170.DOI: 10. 1016/j. expneurol. 2015. 12. 014.
[13]	Viereck J, Thum T. Circulating noncoding RNAs as biomarkers of cardiovascular disease and injury[J]. Circ Res, 2017, 120(2): 381-399.DOI: 10. 1161/CIRCRESAHA. 116. 308434.
[14]	Dykstra-Aiello C, Jickling GC, Ander BP, et al. Altered expression of long noncoding RNAs in blood after ischemic stroke and proximity to putative stroke risk loci[J]. Stroke, 2016, 47(12): 2896-2903.DOI: 10. 1161/STROKEAHA. 116. 013869.
[15]	Tcherpakov M, Delaunay A, Toth J, et al. Regulation of endoplasmic reticulum-associated degradation by RNF5-dependent ubiquitination of JNK-associated membrane protein(JAMP)[J]. J Biol Chem, 2009, 284(18): 12099-12109.DOI: 10. 1074/jbc. M808222200.
[16]	Bromberg KD, Kluger HM, Delaunay A, et al. Increased expression of the E3 ubiquitin ligase RNF5 is associated with decreased survival in breast cancer[J]. Cancer Res, 2007, 67(17): 8172-8179.DOI: 10. 1158/0008-5472. CAN-07-0045.
[17]	陈贵海.炎症与缺血性脑卒中[J].中华神经科杂志, 2010, 43(8): 531-533.DOI: 10. 3760/cma. j. issn. 1006-7876. 2010. 08. 002. Cheng GH. Inflammation and ischemic stroke[J]. Chin J Neurol, 2010, 43(8): 531-533. DOI: 10. 3760/cma. j. issn. 1006-7876. 2010. 08. 002.