基于孟德尔随机化的缺血性脑卒中和膜性肾病发病的因果关系研究

柳怡敏; 张丽娥; 彭阳; 李振宁; 邹云锋

doi:10.16462/j.cnki.zhjbkz.2024.05.011

基于孟德尔随机化的缺血性脑卒中和膜性肾病发病的因果关系研究

doi: 10.16462/j.cnki.zhjbkz.2024.05.011

柳怡敏^{1, 2, 3},
张丽娥^{2, 3, 4},
彭阳^{2, 3, 4},
李振宁^{1, 3},
邹云锋^{1, 2, 3, ,}

1.
广西医科大学公共卫生学院卫生毒理学教研室，南宁 530021
2.
广西医科大学广西环境与健康研究重点实验室，南宁 530021
3.
广西高校高发疾病预防与控制研究重点实验室，南宁 530021
4.
广西医科大学公共卫生学院环境卫生学教研室，南宁 530021

基金项目:

国家自然科学基金 82003410

国家自然科学基金 42367063

广西自然科学基金 2019GXNSFGA245002

广西自然科学基金 2023GXNSFBA026109

详细信息

通讯作者:
邹云锋，E-mail: zouyunfeng@gxmu.edu.cn

中图分类号: R743.33;R692.3+1
计量
- 文章访问数: 180
- HTML全文浏览量: 37
- PDF下载量: 11
- 被引次数: 0
出版历程
- 收稿日期: 2023-11-09
- 修回日期: 2024-03-16
- 网络出版日期: 2024-06-05
- 刊出日期: 2024-05-10

The causal association between ischemic stroke and the risk of membranous nephropathy based on two-sample Mendelian randomization

LIU Yimin^{1, 2, 3},
ZHANG Li′e^{2, 3, 4},
PENG Yang^{2, 3, 4},
LI Zhenning^{1, 3},
ZOU Yunfeng^{1, 2, 3
, ,}

1.
Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China
2.
Guangxi Key Laboratory of Environment and Health, Guangxi Medical University, Nanning 530021, China
3.
Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning 530021, China
4.
Department of Environmental Health, School of Public Health, Guangxi Medical University, Nanning 530021, China

Funds:

National Natural Science Foundation of China 82003410

National Natural Science Foundation of China 42367063

Natural Science Foundation of Guangxi Province 2019GXNSFGA245002

Natural Science Foundation of Guangxi Province 2023GXNSFBA026109

More Information

Corresponding author: ZOU Yunfeng, E-mail: zouyunfeng@gxmu.edu.cn

摘要

摘要: 目的采用两样本孟德尔随机化(Mendelian randomization，MR)方法探讨缺血性脑卒中和膜性肾病发病之间的因果关系。方法从全基因组关联分析研究数据中筛出相互独立且与缺血性脑卒中密切相关的单核苷酸多态性(single nucleotide polymorphisms，SNPs)作为工具变量，以比值比作为评估指标，并采用逆方差加权法、加权中位数法和MR-Egger法探讨缺血性脑卒中和膜性肾病发病的因果关联。结果本研究共筛选到17个缺血性脑卒中相关的SNPs。逆方差加权法分析结果显示缺血性脑卒中是膜性肾病的危险因素(OR=1.61，95% CI: 1.11~2.33，P=0.01)。敏感性分析与主分析结果一致，证实了研究的稳健性，异质性检验表明SNPs不存在异质性。结论从遗传学角度，本研究提示缺血性脑卒中和膜性肾病存在关联。因此，加强对缺血性脑卒中患者膜性肾病的筛查和预防具有重要的指导意义，可降低缺血性脑卒中患者发生膜性肾病的风险。
- 缺血性脑卒中 /
- 膜性肾病 /
- 孟德尔随机化 /
- 因果关系
Abstract: Objective To investigate the causal relationship between ischemic stroke and incidence of membranous nephropathy using a Two-sample Mendelian randomization (MR) method. Methods Single nucleotide polymorphisms (SNPs), which were independent of each other and closely associated with ischemic stroke were identified from a Genome-Wide Association analysis. The identified SNPs were used as instrumental variables. Odds ratios were obtained from the MR analyses on the causal association between ischemic stroke and membranous nephropathy using the inverse variance weighted analysis, weighted median method, and MR-Egger method. Results A total of 17 SNPs that were associated with ischemic stroke were identified in this study. The inverse variance weighted analysis showed that ischemic stroke was associated with higher risk of membranous nephropathy (OR=1.61, 95% CI: 1.11-2.33, P=0.01). Results of the sensitivity analysis were consistent with those of the main analysis, confirming the robustness of this study. No heterogeneity among SNPs was observed in this study. Conclusions From a genetic perspective, the present study suggested an association between ischaemic stroke and elevated risk of membranous nephropathy. Strengthening screening and prevention of membranous nephropathy among patients diagnosed with ischemic stroke is of great clinical and public health significance.
- Ischemic stroke /
- Membranous nephropathy /
- Mendelian randomization /
- Causal inference

HTML全文

图 1 缺血性脑卒中与膜性肾病关系的散点图

Figure 1. The scatter plot of the relationship between ischemic stroke and membranous nephropathy

下载: 全尺寸图片幻灯片

表 1 缺血性脑卒中和膜性肾病的SNPs特征

Table 1. The SNPs features of ischemic stroke and membranous nephropathy

序号 No.	SNPs	CHR	EA	OA	和IS的关系Association with IS				和MN的关系Association with MN
序号 No.	SNPs	CHR	EA	OA	β值value	s_x	P值value	F值value	β值value	s_x	P值value
1	rs1052053	1	G	A	-0.06	0.01	＜0.05	43.83	0.02	0.04	＜0.05
2	rs1053007	19	G	A	0.05	0.01	＜0.05	30.31	0.06	0.05	＜0.05
3	rs11957829	5	G	A	-0.07	0.01	＜0.05	33.62	-0.02	0.05	＜0.05
4	rs12445022	16	A	G	0.06	0.01	＜0.05	41.09	0.02	0.04	＜0.05
5	rs17035646	1	A	G	0.05	0.01	＜0.05	37.10	0.04	0.04	＜0.05
6	rs2005108	11	T	C	0.08	0.01	＜0.05	30.44	0.15	0.06	＜0.05
7	rs2107595	7	A	G	0.08	0.01	＜0.05	55.37	0.08	0.05	＜0.05
8	rs3184504	12	C	T	-0.08	0.01	＜0.05	58.73	-0.02	0.04	＜0.05
9	rs35436	12	T	C	-0.05	0.01	＜0.05	30.93	-0.01	0.04	＜0.05
10	rs42039	7	T	C	-0.07	0.01	＜0.05	33.70	0.00	0.05	＜0.05
11	rs4932370	15	A	G	0.05	0.01	＜0.05	30.48	0.02	0.05	＜0.05
12	rs4959130	6	A	G	0.08	0.01	＜0.05	35.32	0.07	0.06	＜0.05
13	rs6825454	4	C	T	0.06	0.01	＜0.05	37.58	0.03	0.05	＜0.05
14	rs7304841	12	C	A	-0.05	0.01	＜0.05	29.57	-0.02	0.04	＜0.05
15	rs7859727	9	T	C	0.05	0.01	＜0.05	37.44	-0.05	0.04	＜0.05
16	rs9526212	13	G	A	0.06	0.01	＜0.05	37.08	0.06	0.05	＜0.05
17	rs9909858	17	C	T	0.09	0.02	＜0.05	30.39	0.03	0.08	＜0.05
注：SNPs，单核苷酸多态性；CHR，染色体号；EA，效应等位基因；OA，非效应等位基因；IS，缺血性脑卒中; MN，膜性肾病。 Note：SNPs，single nucleotide polymorphisms；CHR，chromosome number；EA，effector allele；OA，non-effect allele; IS, ischemic stroke; MN, membranous nephropathy.

下载: 导出CSV

表 2 3种MR分析方法

Table 2. Three MR analysis methods

MR方法methods	SNPs	β值value	s_x	OR值value(95% CI)	P值value
IVW	17	0.476	0.189	1.61(1.11~2.33)	0.01
MR-Egger	17	1.493	1.022	4.45(0.60~33.02)	0.16
加权中位数Weighted median	17	0.355	0.255	1.43(0.87~2.35)	0.16
注：MR, 孟德尔随机化; IVW, 逆方差加权法; SNPs, 单核苷酸多态性。 Note：MR, mendelian randomization; IVW, Inverse variance weighting method; SNPs, single nucleotide polymorphisms.

下载: 导出CSV

参考文献(24)

[1]	Li JN, Cui Z, Long JY, et al. Primary glomerular nephropathy among hospitalized patients in a national database in China[J]. Nephrol Dial Transplant, 2018, 33(12): 2173-2181. DOI: 10.1093/ndt/gfy022.
[2]	Xu X, Wang GB, Chen N, et al. Long-term exposure to air pollution and increased risk of membranous nephropathy in China[J]. J Am Soc Nephrol, 2016, 27(12): 3739-3746. DOI: 10.1681/ASN.2016010093.
[3]	张慧, 杨薇, 魏丹, 等. 中国终末期肾病患者认知障碍影响因素的Meta分析[J]. 中国全科医学, 2022, 25(21): 2651-2660. DOI: 10.12114/j.issn.1007-9572.2022.0203. Zhang H, Yang W, Wei D, et al. Factors associated with cognitive impairment in Chinese patients with end-stage renal disease: a meta-analysis[J]. Chin Gen Prac, 2022, 25(21): 2651-2660. DOI: 10.12114/j.issn.1007-9572.2022.0203.
[4]	Feigin VL, Owolabi MO. Pragmatic solutions to reduce the global burden of stroke: a world stroke organization-lancet neurology commission[J]. Lancet Neurology, 2023, 22(12): 1160-1206. DOI: 10.1016/S1474-4422(23)00277-6.
[5]	Kumai Y, Kamouchi M, Hata J, et al. Proteinuria and clinical outcomes after ischemic stroke[J]. Neurology, 2012, 78(24): 1909-1915. DOI: 10.1212/WNL.0b013e318259e110.
[6]	Chwojnicki K, Król E, Wierucki Ł, et al. Renal dysfunction in post-stroke patients[J]. PLoS One, 2016, 11(8): e0159775. DOI: 10.1371/journal.pone.0159775.
[7]	Zou HH, Li YB, Xu GS. Management of anticoagulation and antiplatelet therapy in patients with primary membranous nephropathy[J]. BMC Nephrol, 2019, 20(1): 442. DOI: 10.1186/s12882-019-1637-y.
[8]	和思敏, 张雨, 彭刘庆, 等. 倾向性评分与孟德尔随机化国内研究现状[J]. 中华疾病控制杂志, 2022, 26(3): 325-330. DOI: 10.16462/j.cnki.zhjbkz.2022.03.014. He SM, Zhang Y, Peng LQ, et al. Research progress of propensity score and Mendelian randomization in China[J]. Chin J Dis Control Prev, 2022, 26(3): 325-330. DOI: 10.16462/j.cnki.zhjbkz.2022.03.014.
[9]	Malik R, Chauhan G, Traylor M, et al. Publisher Correction: Multiancestry genome-wide association study of 520, 000 subjects identifies 32 loci associated with stroke and stroke subtypes[J]. Nat Genet, 2019, 51(7): 1192-1193. DOI: 10.1038/s41588-019-0449-0.
[10]	Xie JY, Liu LL, Mladkova N, et al. The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis[J]. Nat Commun, 2020, 11(1): 1600. DOI: 10.1038/s41467-020-15383-w.
[11]	Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data[J]. Genet Epidemiol, 2013, 37(7): 658-665. DOI: 10.1002/gepi.21758.
[12]	Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted Median estimator[J]. Genet Epidemiol, 2016, 40(4): 304-314. DOI: 10.1002/gepi.21965.
[13]	Zhang Y, Liu ZP, Choudhury T, et al. Habitual coffee intake and risk for nonalcoholic fatty liver disease: a two-sample Mendelian randomization study[J]. Eur J Nutr, 2021, 60(4): 1761-1767. DOI: 10.1007/s00394-020-02369-z.
[14]	Weiner DE, Tighiouart H, Amin MG, et al. Chronic kidney diease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies[J]. J Am Soc Nephrol, 2004, 15(5): 1307-1315. DOI: 10.1097/01.asn.0000123691.46138.e2.
[15]	Zhang J, Shu JL, You Q, et al. Ischemic stroke in anti-phospholipase A2 receptor antibody-positive primary membranous nephropathy: clinical and neuroimaging characteristics[J]. Chin Med J, 2020, 133(3): 361-363. DOI: 10.1097/CM9.0000000000000610.
[16]	Hoxha E, Reinhard L, Stahl RAK. Membranous nephropathy: new pathogenic mechanisms and their clinical implications[J]. Nat Rev Nephrol, 2022, 18(7): 466-478. DOI: 10.1038/s41581-022-00564-1.
[17]	Zhang CY, Wang XB, He ML, et al. Proteinuria is an independent risk factor for first incident stroke in adults under treatment for hypertension in China[J]. J Am Heart Assoc, 2015, 4(12): e002639. DOI: 10.1161/JAHA.115.002639.
[18]	Pallavi R, Sunggeun L, Baumstein D, et al. Stroke in a young woman as a presenting manifestation of membranous nephropathy[J]. Am J Ther, 2016, 23(3): e950-e954. DOI: 10.1097/MJT.0000000000000075.
[19]	Mohammadian R, Tarighatnia A, Naghibi M, et al. Vertebrobasilar artery stroke as the heralding sign of systemic lupus erythematosus[J]. J Stroke Cerebrovasc Dis, 2018, 27(5): e80-e85. DOI: 10.1016/j.jstrokecerebrovasdis.2017.12.003.
[20]	Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke[J]. N Engl J Med, 2018, 378(17): 1573-1582. DOI: 10.1056/NEJMoa1716405.
[21]	Hârza M, Ismail G, Mitroi G, et al. Histological diagnosis and risk of renal vein thrombosis, and other thrombotic complications in primitive nephrotic syndrome[J]. Rom J Morphol Embryol, 2013, 54: 555-560. DOI: 2013;54(3):555-560.
[22]	Xie Z, Tong S, Chu X, et al. Chronic kidney disease and cognitive impairment: the kidney-brain axis[J]. Kidney Dis(Basel), 2022, 8(4): 275-285. DOI: 10.1159/000524475.
[23]	El Husseini N, Fonarow GC, Smith EE, et al. Association of kidney function with 30-day and 1-year poststroke mortality and hospital readmission[J]. Stroke, 2018, 49(12): 2896-2903. DOI: 10.1161/STROKEAHA.118.022011.
[24]	Zhao Q, Yan T, Chopp M, et al. Brain-kidney interaction: renal dysfunction following ischemic stroke[J]. J Cereb Blood Flow Metab, 2020, 40(2): 246-262. DOI: 10.1177/0271678X19890931.