基于两样本单变量和多变量孟德尔随机化研究铁稳态与缺血性脑卒中后功能结局的因果关联

陈世宣; 陈珍珍; 陈温慈; 计静

doi:10.16766/j.cnki.issn.1674-4152.004281

基于两样本单变量和多变量孟德尔随机化研究铁稳态与缺血性脑卒中后功能结局的因果关联

doi: 10.16766/j.cnki.issn.1674-4152.004281

1.
浙江中医药大学附属温州市中西医结合医院康复医学科，浙江温州 325000
2.
浙江中医药大学附属温州市中西医结合医院护理部

基金项目:

浙江省中医药科技计划项目 2021ZB276

温州市科技局科研项目 Y20240897

详细信息

通讯作者:
计静，E-mail：jjing@alu.zcmu.edu.cn

中图分类号: R743.3
计量
- 文章访问数: 5
- HTML全文浏览量: 2
- PDF下载量: 0
- 被引次数: 0
出版历程
- 收稿日期: 2024-12-25
- 网络出版日期: 2026-03-13

Causal association between iron homeostasis and functional outcome after ischemic stroke: a two-sample univariate and multivariate Mendelian randomization study

1.
Department of Rehabilitation Medicine, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Zhejiang Chinese Medical University, Wenzhou, Zhejiang 325000, China

摘要

摘要: 目的观察性研究表明血清铁稳态与缺血性脑卒中后功能结局相关，但该关联易受混杂因素和反向因果影响。本研究采用孟德尔随机化(MR)方法以减少混杂因素干扰，评估铁稳态失衡是否与缺血性脑卒中后不良功能结局存在因果关联。方法选择铁稳态相关的全基因组关联研究(GWAS)数据，包括血清铁、铁蛋白、总铁结合力、转铁蛋白饱和度和肝脏铁含量，作为暴露变量；缺血性脑卒中3个月后功能结局的GWAS数据作为结局变量。首先进行两样本单变量MR(UVMR)分析，随机效应逆方差加权(IVW)作为本研究的主要分析方法，MR-Egger和加权中位数(WME)作为补充性分析方法。Cochran's Q和Rucker's Q检验用于检查异质性，MR-Egger截距用于检验水平多效性。此外，本研究还执行了多变量MR(MVMR)分析，以评估校正BMI后的因果效应。结果最终筛选出117个单核苷酸多态性(SNPs)作为铁稳态指标的工具变量，所有SNPs的F值均＞10。UVMR-IVW结果显示，血清铁、血清转铁蛋白饱和度和肝脏铁含量与缺血性脑卒中3个月后不良功能结局之间存在因果关联(P＜0.05)。校正BMI的MVMR-IVW结果显示，血清铁和血清转铁蛋白饱和度与缺血性脑卒中3个月后不良功能结局之间仍保持显著的因果关联(P＜0.05)。所有结果MR-Egger和WME法的方向与IVW一致，且均未发现异质性和水平多效性证据。结论血清铁过载与缺血性脑卒中3个月后不良功能结局之间存在显著的因果关联。
- 缺血性脑卒中 /
- 铁稳态 /
- 功能结局 /
- 因果关联 /
- 孟德尔随机化
Abstract: Objective Observational studies suggest an association between serum iron homeostasis and functional outcome after ischemic stroke, but this association is susceptible to confounders and reverse causality. This study utilizes Mendelian randomization (MR) to minimize confounders and assess whether an imbalance in iron homeostasis is causally associated with poor functional outcome after ischemic stroke. Methods GWAS data related to iron homeostasis, including serum iron, ferritin, total iron-binding capacity, transferrin saturation, and liver iron content, were selected as exposure variables. GWAS data on functional outcome at three months after ischemic stroke were used as outcome variables. Firstly, univariable MR (UVMR) analysis was conducted, with the random effects inverse variance weighting (IVW) serving as the primary analysis method, and MR-Egger and weighted median (WME) methods as supplementary analyses. Cochran's Q and Rucker's Q tests were employed to assess heterogeneity, while the MR-Egger intercept was used to test for horizontal pleiotropy. Additionally, multivariable MR (MVMR) analysis was performed to evaluate the causal effect after adjusting for BMI. Results A total of 117 single nucleotide polymorphisms (SNPs) were ultimately selected as instrumental variables for iron homeostasis, with all SNPs having an F-value greater than 10. The UVMR-IVW results indicated a causal association between serum iron, transferrin saturation, liver iron content, and poor functional outcome at three months after ischemic stroke (P < 0.05). The MVMR-IVW results, adjusted for BMI, showed that serum iron and transferrin saturation maintained significant causal associations with poor functional outcome at three months after ischemic stroke (P < 0.05). All results from MR-Egger and WME methods were consistent with IVW, and no evidence of heterogeneity or horizontal pleiotropy was found. Conclusion There is a significant causal association between serum iron overload and poor functional outcome at three months after ischemic stroke.
- Ischemic stroke /
- Iron homeostasis /
- Functional outcome /
- Causality /
- Mendelian randomization

HTML全文

表 1 暴露、混杂和结局变量GWAS数据的详细信息

Table 1. Detailed information on GWAS data for exposure, confounding, and outcome variables

变量	数据来源	样本量(例)	研究人群	PMID
血清铁	BELL S等^[8]	163 511	欧洲人群	33536631
铁蛋白	BELL S等^[8]	246 139	欧洲人群	33536631
总铁结合力	BELL S等^[8]	135 430	欧洲人群	33536631
转铁蛋白饱和度	BELL S等^[8]	131 471	欧洲人群	33536631
肝脏铁含量	LIU Y等^[9]	32 858	欧洲人群	34128465
BMI	UK Biobank	461 460	欧洲人群
卒中后功能结局	GISCOME联盟	2 280个病例和3 741个对照	欧洲人群	30796134

下载: 导出CSV

表 2 UVMR的主要研究结果

Table 2. The main research findings of UVMR

暴露变量	结局变量	工具变量数	方法	OR(95% CI)	P值	异质性P值	多效性P值
血清铁	卒中后功能结局	22	IVW	1.461(1.104~1.935)	0.008	0.999	0.509
		22	MR-Egger	1.822(0.795~4.177)	0.172	0.999
		22	WME	1.873(0.936~3.750)	0.077
铁蛋白	卒中后功能结局	41	IVW	1.205(0.909~1.597)	0.194	1.000	0.804
		41	MR-Egger	1.322(0.559~3.123)	0.529	1.000
		41	WME	1.245(0.649~2.390)	0.510
总铁结合力	卒中后功能结局	26	IVW	0.867(0.653~1.152)	0.326	0.960	0.708
		26	MR-Egger	0.801(0.457~1.402)	0.444	0.948
		26	WME	0.810(0.469~1.402)	0.452
转铁蛋白饱和度	卒中后功能结局	25	IVW	1.250(1.015~1.539)	0.036	0.996	0.159
		25	MR-Egger	1.713(1.001~2.934)	0.062	0.999
		25	WME	1.251(0.809~1.934)	0.315
肝脏铁含量	卒中后功能结局	3	IVW	1.428(1.075~1.895)	0.014	0.566	0.490
		3	MR-Egger	1.202(0.731~1.977)	0.601	0.781
		3	WME	1.396(0.956~2.040)	0.084

下载: 导出CSV

表 3 MVMR的主要研究结果

Table 3. Main findings of MVMR analysis

暴露变量	混杂变量	结局变量	工具变量数	方法	OR (95% CI)	P值	异质性P值	多效性P值
血清铁	BMI	卒中后功能结局	401	IVW	1.916(1.109~3.311)	0.020	0.859	0.982
			401	MR-Egger	1.922(1.042~3.547)	0.037	0.851
			401	WME	1.962(0.885~4.349)	0.097
转铁蛋白饱和度	BMI	卒中后功能结局	397	IVW	1.654(1.040~2.630)	0.033	0.760	0.278
			397	MR-Egger	1.460(0.872~2.445)	0.150	0.762
			397	WME	1.702(0.906~3.199)	0.098
肝脏铁含量	BMI	卒中后功能结局	389	IVW	1.243(0.890~1.735)	0.201	0.778	0.054
			389	MR-Egger	1.449(1.002~2.094)	0.049	0.807
			389	WME	1.332(0.813~2.183)	0.256

下载: 导出CSV

参考文献(30)

[1]	王陇德, 彭斌, 张鸿祺, 等. 《中国脑卒中防治报告2020》概要[J]. 中国脑血管病杂志, 2022, 19(2): 136-144. WANG L D, PENG B, ZHANG H Q, et al. Brief report on stroke prevention and treatment in China, 2020[J]. Chin J Cerebrovasc Dis, 2022, 19(2): 136-144.
[2]	HAN J, ZHANG J, YAO X, et al. Mechanism of HDAC1 regulating iron overload-induced neuronal oxidative damage after cerebral hemorrhage[J]. Mol Neurobiol, 2024, 61(10): 7549-7566. doi: 10.1007/s12035-024-04000-2
[3]	SAKIB A A, MIAH M, ALAM M K, et al. Relation of serum ferritin level with severity of neurological disability among patients with acute ischemic stroke[J]. Mymensingh Med J, 2024, 33(4): 973-979.
[4]	陈娟, 陈世宣, 王丰, 等. 血清铁相关指标与脑卒中后认知障碍风险的相关性[J]. 中华全科医学, 2024, 22(11): 1876-1879. doi: 10.16766/j.cnki.issn.1674-4152.003754 CHEN J, CHEN S X, WANG F, et al. Correlation analysis between serum iron-related indicators and the risk of post-stroke cognitive impairment in stroke patients[J]. Chinese Journal of General Practice, 2024, 22(11): 1876-1879. doi: 10.16766/j.cnki.issn.1674-4152.003754
[5]	YEH S J, CHEN C H, LIN Y H, et al. Association of ferroptosis with severity and outcomes in acute ischemic stroke patients undergoing endovascular thrombectomy: a case-control study[J]. Mol Neurobiol, 2023, 60(10): 5902-5914. doi: 10.1007/s12035-023-03448-y
[6]	WU Q, WEI C, LIU J, et al. Effects of hyperferritinemia on functional outcome in acute ischemic stroke patients with admission hyperglycemia[J]. Cerebrovasc Dis, 2023, 52(5): 511-518. doi: 10.1159/000527860
[7]	RICHMOND R C, DAVEY S G. Mendelian randomization: concepts and scope[J]. Cold Spring Harb Perspect Med, 2022, 12(1): a40501. DOI: 10.1101/cshperspect.a040501.
[8]	BELL S, RIGAS A S, MAGNUSSON M K, et al. A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis[J]. Commun Biol, 2021, 4(1): 156. DOI: 10.1038/s42003-020-01575-z.
[9]	LIU Y, BASTY N, WHITCHER B, et al. Genetic architecture of 11 organ traits derived from abdominal MRI using deep learning[J]. Elife, 2021, 10(6): e65554. DOI: 10.7554/eLife.65554.
[10]	SODERHOLM M, PEDERSEN A, LORENTZEN E, et al. Genome-wide association meta-analysis of functional outcome after ischemic stroke[J]. Neurology, 2019, 92(12): e1271-e1283.
[11]	CHEN S, CHEN Z, XU Q, et al. Dual effects of serum urate on stroke risk and prognosis: insights from Mendelian randomization[J]. Front Neurol, 2024, 15: 1359292. DOI: 10.3389/fneur.2024.1359292.
[12]	TIAN Y, TIAN Y, YUAN Z, et al. Iron metabolism in aging and age-related diseases[J]. Int J Mol Sci, 2022, 23(7): 3612. DOI: 10.3390/ijms23073612.
[13]	FAN X, LI A, YAN Z, et al. From iron metabolism to ferroptosis: pathologic changes in coronary heart disease[J]. Oxid Med Cell Longev, 2022, 2022(8): 6291889. DOI: 10.1155/2022/6291889.
[14]	HU H, CHEN Y, JING L, et al. The link between ferroptosis and cardiovascular diseases: a novel target for treatment[J]. Front Cardiovasc Med, 2021, 8(7): 710963. DOI: 10.3389/fcvm.2021.710963.
[15]	LEVI S, RIPAMONTI M, MORO A S, et al. Iron imbalance in neurodegeneration[J]. Mol Psychiatry, 2024, 29(4): 1139-1152. doi: 10.1038/s41380-023-02399-z
[16]	BU Z Q, YU H Y, WANG J, et al. Emerging role of ferroptosis in the pathogenesis of ischemic stroke: a new therapeutic target?[J]. ASN Neuro, 2021, 13: 523058879. DOI: 10.1177/17590914211037505.
[17]	MAO H, DOU W, WANG X, et al. Iron deposition in fray matter nuclei of patients with intracranial artery stenosis: a quantitative susceptibility mapping study[J]. Front Neurol, 2021, 12: 785822. DOI: 10.3389/fneur.2021.785822.
[18]	KATAIKE V M, DESMOND P M, STEWARD C, et al. Iron changes within infarct tissue in ischemic stroke patients after successful reperfusion quantified using QSM[J]. Neuroradiology, 2024, 66(12): 2233-2242. doi: 10.1007/s00234-024-03444-6
[19]	JIN Y, HUANG Y H, CHEN Y P, et al. Combined effect of cortical superficial siderosis and cerebral microbleed on short-term and long-term outcomes after intracerebral haemorrhage[J]. Stroke Vasc Neurol, 2024, 9(4): 429-438. doi: 10.1136/svn-2023-002439
[20]	RAJENDRAN S R, PERIYASAMY S, MANJULADEVI M T, et al. Evaluation of serum ferritin as a prognostic marker in acute hemorrhagic stroke[J]. J Neurosci Rural Pract, 2020, 11(1): 72-77.
[21]	SAKIB A A, MIAH M, ALAM M K, et al. Relation of serum ferritin level with severity of neurological disability among patients with acute ischemic stroke[J]. Mymensingh Med J, 2024, 33(4): 973-979.
[22]	HE Q, WANG W, XU D, et al. Causal association of iron status with functional outcome after ischemic stroke[J]. Stroke, 2024, 55(2): 423-431. doi: 10.1161/STROKEAHA.123.044930
[23]	DU B, DENG Z, CHEN K, et al. Iron promotes both ferroptosis and necroptosis in the early stage of reperfusion in ischemic stroke[J]. Genes Dis, 2024, 11(6): 101262. DOI: 10.1016/j.gendis.2024.101262.
[24]	MILLAN M, DEGREGORIO-ROCASOLANO N, PEREZ D L O N, et al. Targeting pro-oxidant iron with deferoxamine as a treatment for ischemic stroke: safety and optimal dose selection in a randomized clinical trial[J]. Antioxidants(Basel), 2021, 10(8): 1270. DOI: 10.3390/antiox10081270.
[25]	DELGADO-MARTIN S, MARTINEZ-RUIZ A. The role of ferroptosis as a regulator of oxidative stress in the pathogenesis of ischemic stroke[J]. FEBS Lett, 2024, 598(17): 2160-2173. doi: 10.1002/1873-3468.14894
[26]	YE Y, XIE X, BI Y, et al. Naoqing formula alleviates acute ischaemic stroke-induced ferroptosis via activating Nrf2/xCT/GPX4 pathway[J]. Front Pharmacol, 2024, 15: 1525456. DOI: 10.3389/fphar.2024.1525456.
[27]	ZHAO Y, LIU Y, XU Y, et al. The role of ferroptosis in blood-brain barrier injury[J]. Cell Mol Neurobiol, 2023, 43(1): 223-236. doi: 10.1007/s10571-022-01197-5
[28]	ZHAO Y, YANG M, LIANG X. The role of mitochondria in iron overload-induced damage[J]. J Transl Med, 2024, 22(1): 1057. DOI: 10.1186/s12967-024-05740-4.
[29]	NADGAUDA K P, METGUD D C, BELLAD R M, et al. Exploring the association between haematological markers of iron and general movements in 4-month-old infants exposed to anaemia in-utero[J]. Early Hum Dev, 2024, 195: 106080. DOI: 10.1016/j.earlhumdev.2024.106080.
[30]	MAIO N, SANETO R P, STEET R, et al. Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures[J]. Brain Commun, 2022, 4(3): fcac102. DOI: 10.1093/braincomms/fcac102.