TIMP-2基因-418G/C多态性与房颤性脑梗死的关系研究

李卫玲; 金笑平; 虞丹; 沈玉光

doi:10.16766/j.cnki.issn.1674-4152.002365

TIMP-2基因-418G/C多态性与房颤性脑梗死的关系研究

doi: 10.16766/j.cnki.issn.1674-4152.002365

浙江省台州医院神经内科，浙江临海 317000

基金项目:

浙江省基础公益研究项目 LGF18H090019

浙江省医药卫生科技计划项目 2020KY1035

详细信息

通讯作者:
金笑平，E-mail: jinxp@enzemed.com

中图分类号: R743.33
计量
- 文章访问数: 236
- HTML全文浏览量: 104
- PDF下载量: 3
- 被引次数: 0
出版历程
- 收稿日期: 2021-03-12
- 网络出版日期: 2022-08-13

Association between matrix metalloproteinase inhibitor-2 gene -418G/C polymorphisms and cerebral infarction with atrial fibrillation

Department of Neurology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, China

摘要

摘要: 目的心房颤动引起的梗死是目前缺血性卒中患者高死亡率的主要原因之一，基于基质金属蛋白酶抑制因子(TIMP)在房颤心肌维化过程中重要作用，本文探讨了TIMP-2基因启动子-418G/C多态性与房颤引起脑梗死的关系。方法采用聚合酶链反应-限制性片段长多态性法对2016年1月—2018年6月浙江省台州医院神经内科首次因房颤性脑梗死住院患者204例(观察组)及非心源性脑梗死248例(对照组)进行TIMP-2基因启动子区-418G/C多态性检测，并对2组患者的一般情况及基因型、等位基因等进行比较。结果观察组和对照组性别、年龄、吸烟、饮酒、入院时收缩压及舒张压、空腹血糖、甘油三酯、总胆固醇、低密度脂蛋白胆固醇、纤维蛋白原、同型半胱氨酸等差异均无统计学意义(均P＞0.05)。观察组GC+CC基因型共94例(46.1%)，对照组GC+CC基因型共90例(36.3%)，2组比较差异有统计学意义(P=0.043，95% CI：1.017~1.585)，观察组C等位基因115例(28.2%)，与对照组[106例(21.4%)]比较差异有统计学意义(P=0.020, 95% CI：1.049~1.658)。结论 TIMP-2基因-418G/C位点多态性与房颤性脑梗死遗传易感性可能相关。
- 基质金属蛋白酶抑制因子-2 /
- 房颤 /
- 脑梗死 /
- 基因多态性
Abstract: Objective Cerebral infarction caused by atrial fibrillation is a principal cause of high mortality in patients with ischaemic stroke. Considering the important role of matrix metalloproteinase inhibitor (TIMP) in the myocardial dimension process of atrial fibrillation, this study investigates the relationship between promoter region polymorphism (-418G/C) of TIMP-2 and cerebral infarction caused by atrial fibrillation. Methods Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect TIMP-2 gene promoter region -418G/C site polymorphism in 204 cases of cerebral infarction of atrial fibrillation (case group) and 248 cases of noncardiogenic cerebral infarction (control group) with first admission between January 2016 and June 2018. The general, genotype and all of the groups were compared. Results No significant differences in gender, age, tobacco and alcohol habits, systolic and diastolic blood pressure at admission, fasting glucose, triglyceride, total cholesterol, low-density lipoprotein cholesterol, fibrinogen and homocysteine were found between the case and control groups (all P>0.05). A total of 94 cases of the case group in GC+CC genotype accounted for 46.1%, and 90 cases of the control group in GC+CC genotype accounted for 36.3%; the difference between the two groups was statistically significant (P=0.043, 95% CI: 1.017-1.585). On the time, there were 115 cases of the case group in C allele, accounting for 28.2%, while 106 cases of the control group, accounting for 21.4%. The difference between the two groups was statistically significant (P=0.020, 95% CI: 1.049-1.658). Conclusion The TIMP-2 (-418gG/C) polymorphism may be associated with genetic susceptibility in cerebral infarction with atrial fibrillation.
- Matrix metalloproteinase inhibitor 2 /
- Atrial fibrillation /
- Cerebral infarction /
- Genetic polymorphism

HTML全文

图 1 TIMP-2PCR扩增产物经限制性内切酶Eco88 I酶切图

注：泳道1为100 bp DNA标志物；泳道2、15为GC基因型(253、230、51和23 bp)；泳道3为CC基因型(253、51 bp)；泳道4~14、16为GG基因型(230、51、23 bp)；其中51、23 bp已跑出胶外，故图中未显示。

Figure 1. Electrophoresis of TIMP-2 (-418G/C) product digested with Eco88 I restriction enzyme

下载: 全尺寸图片幻灯片

表 1 2组脑梗死患者一般资料比较

Table 1. Comparison of baseline data between two groups with cerebral infarction

组别	例数	性别 (男/女, 例)	年龄 (x±s, 岁)	高血压病 [例(%)]	2型糖尿病 [例(%)]	吸烟 [例(%)]	饮酒 [例(%)]	收缩压 (x±s, mm Hg)	舒张压 (x±s, mm Hg)	空腹血糖 (x±s, mmol/L)
观察组	204	132/72	68.97±11.30	107(52.5)	47(23.0)	79(38.7)	49(24.0)	147.11±21.48	85.78±12.95	6.13±2.33
对照组	248	144/104	68.53±10.10	146(58.9)	42(16.9)	78(31.5)	49(19.8)	143.91±21.62	83.94±11.03	5.67±1.93
统计量		2.083^a	0.033^b	1.872^a	0.626^a	2.608^a	0.193^a	1.246^b	1.190^b	1.529^b
P值		0.175	0.973	0.183	0.122	0.113	0.303	0.213	0.235	0.127

组别	例数	甘油三酯 [M(P₂₅, P₇₅), mmol/L]		总胆固醇 (x±s, mmol/L)	高密度脂蛋白胆固醇 [M(P₂₅, P₇₅), mmol/L]		低密度脂蛋白胆固醇 (x±s, mmol/L)	纤维蛋白原 (x±s, g/L)		同型半胱氨酸 [M(P₂₅, P₇₅)，μmol/L]
观察组	204	1.14(0.85, 1.44)		4.55±1.24	1.25(1.05, 1.51)		2.59±0.83	3.44±1.08		11.30(6.10, 16.65)
对照组	248	1.27(0.82, 1.85)		4.67±1.01	1.25(1.09, 1.44)		2.71±0.84	3.34±0.92		11.00(8.90, 13.80)
统计量		-1.130^c		0.570^b	-0.121^c		1.195^b	0.574^b		-0.298^c
P值		0.258		0.569	0.903		0.233	0.566		0.766
注：^a为χ²值，^b为t值，^c为Z值。1 mm Hg=0.133 kPa。

下载: 导出CSV

表 2 2组脑梗死患者基因型频率比较[例(%)]

Table 2. Comparison of genotype frequency between two groups with cerebral infarction [case (%)]

组别	例数	基因型GG	基因型GC+CC	χ²值	P值
观察组	204	110(53.9)	73+21(46.1)	4.441	0.043
对照组	248	158(63.7)	74+16(36.3)
注：OR=1.270，95% CI为1.017~1.585。

下载: 导出CSV

表 3 2组脑梗死患者等位基因频率比较[例(%)]

Table 3. Comparison of allele frequency between two groups with cerebral infarction [case (%)]

组别	例数	等位基因G	等位基因C	χ²值	P值
观察组	204	293(71.8)	115(28.2)	5.609	0.020
对照组	248	390(78.6)	106(21.4)
注：OR=1.319，95% CI为1.049~1.658。

下载: 导出CSV

表 4 非条件logistic回归分析结果

Table 4. Results of unconditional logistic regression analysis

变量	B	SE	Wald χ²	P值	OR值	95% CI
性别	-0.281	0.234	1.447	0.229	0.755	0.477~1.194
高血压史	-0.330	0.213	2.408	0.121	0.719	0.474~1.091
糖尿病史	0.247	0.281	0.772	0.379	1.280	0.738~2.222
吸烟史	0.174	0.237	0.540	0.463	1.191	0.748~1.896
空腹血糖	0.670	0.231	8.456	0.004	1.955	1.244~3.071
TIMP-2(-418G/C)GC+CC基因型	0.287	0.200	2.055	0.152	1.332	0.900~1.972
注：变量赋值如下，性别，女性=0，男性=1；高血压史，无=0，有=1；糖尿病史，无=0，有=1;吸烟史，无=0，有=1；空腹血糖≤5.9 mmol/L=0, 空腹血糖＞5.9 mmol/L=1;基因型，GG=0，GC+CC=1。

下载: 导出CSV

参考文献(22)

[1]	陈伟伟, 高润霖, 刘力生, 等. 《中国心血管病报告2017》概要[J]. 中国循环杂志, 2018, 33(1): 1-8. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGXH201801001.htm CHEN W W, GAO R L, LIU L S, et al. Summary of China cardiovascular disease report 2017[J]. Chin Circ J, 2018, 33(1): 1-8. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGXH201801001.htm
[2]	JANUARY C T, WANN L S, CALKINS H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American college of Cardiology/American Heart Association task force on clinical practice guidelines and the heart rhythm society[J]. Heart Rhythm, 2019, 16(8): e66-e93. doi: 10.1016/j.hrthm.2019.01.024
[3]	CHEN L C, SHIBU M A, LIU C J, et al. ERK1/2 mediates the lipopolysaccharide-induced upregulation of FGF-2, uPA, MMP-2, MMP-9 and cellular migration in cardiac fibroblasts[J]. Chem Biol Interact, 2019, 306: 62-69. doi: 10.1016/j.cbi.2019.04.010
[4]	CAO J W, DUAN S Y, ZHANG H X, et al. Zinc deficiency promoted fibrosis via ROS and TIMP/MMPs in the myocardium of mice[J]. Biol Trace Elem Res, 2020, 196(1): 145-152. doi: 10.1007/s12011-019-01902-4
[5]	LIU Y, XU B, WU N, et al. Association of MMPs and TIMPs with the occurrence of atrial fibrillation: A systematic review and meta-analysis[J]. Can J Cardiol, 2016, 32(6): 803-813. doi: 10.1016/j.cjca.2015.08.001
[6]	ABE I, TESHIMA Y, KONDO H, et al. Association of fibrotic remodeling and cytokines/chemokines content in epicardial adipose tissue with atrial myocardial fibrosis in patients with atrial fibrillation[J]. Heart Rhythm, 2018, 15(11): 1717-1727. doi: 10.1016/j.hrthm.2018.06.025
[7]	HUANG X Y, YE Q, ZHANG Z, et al. Association of matrix metalloproteinase-3 gene 5A/6A polymorphism with the recurrence of ischemic stroke: A prospective observational study[J]. Brain Res, 2017, 1674: 55-61. doi: 10.1016/j.brainres.2017.08.009
[8]	WANG Y K, ZHENG L, HUANG H T, et al. Relationship between the matrix metalloproteinase-9 gene polymorphisms and ischemic stroke[J]. Int J Clin Exp Pathol, 2019, 12(3): 949-956.
[9]	CHEN Y C, HO W M, LEE Y S, et al. TIMP-2 genes are associated with spontaneous deep intracerebral hemorrhage in the Taiwan population[J]. PLoS One, 2015, 10(11): e0142482. DOI: 10.1371/journal.pone.0142482.
[10]	XU P C, GUO W, JIN T B, et al. TIMP-2 SNPs rs7342880 and rs4789936 are linked to risk of knee osteoarthritis in the Chinese Han Population[J]. Oncotarget, 2017, 8(1): 1166-1176. doi: 10.18632/oncotarget.13590
[11]	中华医学会神经病学分会, 中华医学会神经病学分会脑血管病学组. 中国急性缺血性脑卒中诊治指南2018[J]. 中华神经科杂志, 2018, 51(9): 666-682. https://www.cnki.com.cn/Article/CJFDTOTAL-XDJB201911024.htm Chinese society of neurology, Chinese stroke society. Chinese guidelines for diagnosis and treatment of acute ischemic stroke 2018[J]. Chin J Neurol, 2018, 51(9): 666-682. https://www.cnki.com.cn/Article/CJFDTOTAL-XDJB201911024.htm
[12]	HILL V A, TOWFIGHI A. Modifiable risk factors for stroke and strategies for stroke prevention[J]. Semin Neurol, 2017, 37(3): 237-258.
[13]	BAI Y, WANG Y L, SHANTSILA A, et al. The global burden of atrial fibrillation and stroke: A systematic review of the clinical epidemiology of atrial fibrillation in Asia[J]. Chest, 2017, 152(4): 810-820.
[14]	姜亦瑶, 王凯, 施超. 心肌纤维化引起心房颤动的研究进展[J]. 医学信息, 2018, 31(12): 28-30. JIANG Y Y, WANG K, SHI C, et al. Research progress of atrial fibrillation caused by myocardial fibrosis[J]. Med Info, 2018, 31(12): 28-30.
[15]	王凤, 金笑平, 朱敏, 等. MMP-2基因-735C/T多态性与脑梗死患者出血转化风险的相关性研究[J]. 中华全科医学, 2018, 16(3): 352-355, 440. doi: 10.16766/j.cnki.issn.1674-4152.00098 WANG F, JIN X P, ZHU M, et al. Association between MMP-2 (-735 C/T) polymorphism and the risk of hemorrhagic transformation in patients with acute cerebral infarction[J]. Chin J Gen Pract, 2018, 16(3): 352-355, 400. doi: 10.16766/j.cnki.issn.1674-4152.00098
[16]	ZHENG Z, HE X W, ZHU M, et al. Tissue inhibitor of the metalloproteinases-3 gene polymorphisms and carotid plaque susceptibility in the Han Chinese population[J]. Int J Neurosci, 2018, 128(10): 1-28.
[17]	胡晓飞, 朱先华, 刘鹏, 等. 基质金属蛋白酶13血清水平及基因启动子区-77A/G多态性与无症状性颈动脉狭窄的关联分析[J]. 中华全科医学, 2019, 17(7): 1209-1212. doi: 10.16766/j.cnki.issn.1674-4152.000903 HU X F, ZHU X H, LIU P, et al. Association of serum matrix metalloproteinase-13 levels and gene promoter -77A/G functional polymorphism with asymptomatic carotid stenosis[J]. Chin J Gen Pract, 2019, 17(7): 1209-1212. doi: 10.16766/j.cnki.issn.1674-4152.000903
[18]	BREW K. Reflections on the evolution of the vertebrate tissue inhibitors of metalloproteinases[J]. FASEB J, 2019, 33(1): 71-87.
[19]	GUO T, HAO H Z, ZHOU L, et al. Association of SNPs in the TIMP-2 gene and large artery atherosclerotic stroke in southern Chinese Han population[J]. Oncotarget, 2017, 9(4): 4698-4706.
[20]	GURUNG R, CHOONG A M, WOO C C, et al. Genetic and epigenetic mechanisms underlying vascular smooth muscle cell phenotypic modulation in abdominal aortic aneurysm[J]. Int J Mol Sci, 2020, 21(17): 6334.
[21]	BENJAMIN E J, VIRANI S S, CALLAWAY C W, et al. American Heart Association Council on epidemiology and prevention statistics committee and stroke statistics subcommittee: Heart disease and stroke statistics-2018 update: A report from the American Heart Association[J]. Circulation, 2018, 137(12): e67-e492.
[22]	RICHARD L J, SHEIKH A, RAMI B, et al. Neuroinflammation: Friend and foe for ischemic stroke[J]. J Neuroinflammation, 2019, 16(1): 142.