C 反应蛋白与动脉粥样硬化性缺血性卒中的因果关系：一项孟德尔随机化研究。

Causal relationship between C-reactive protein and ischemic stroke caused by atherosclerosis: A Mendelian randomization study.

机构信息

Department of Neurology and Institute of Neurology, First Affiliated Hospital, Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, PR China; Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, PR China.

出版信息

J Stroke Cerebrovasc Dis. 2024 Sep;33(9):107873. doi: 10.1016/j.jstrokecerebrovasdis.2024.107873. Epub 2024 Jul 14.

DOI:10.1016/j.jstrokecerebrovasdis.2024.107873

PMID:39009197

Abstract

OBJECTIVES

This study investigates the association between C-reactive protein (CRP) and ischemic stroke caused by large artery atherosclerosis (LAA).

METHODS

Five Mendelian Randomization (MR) methodologies were used for two-sample analyses: Inverse Variance Weighting (IVW), MR-Egger regression, Weighted Median (WM), Simple Mode, and Weighted Mode. CRP exposure data were obtained from aggregated summary statistics from a meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry (n = 343,524; UK Biobank). Stroke data were used as the outcome, with specific dataset details for relevant subtypes (cases = 40,585, controls = 406,111).

RESULTS

In the CRP GWAS dataset, selected single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) showed genome-wide significance and a causal relationship with CRP, particularly in relation to LAA stroke. IVW indicated a robust causal connection between CRP and LAA stroke (Beta = 0.151, SE = 0.055, P = 0.006). The WM approach supported this relationship (Beta = 0.176, SE = 0.082, P = 0.033). However, MR-Egger regression suggested a potential absence of a causal link (Beta = 0.098, SE = 0.077, P = 0.206), with minimal influence from horizontal pleiotropy (Intercept = 0.0029; P = 0.317). The Simple mode found no significant association (Beta = 0.046, SE = 0.217, P = 0.834), while the Weighted mode revealed a significant causal association (Beta = 0.138, SE = 0.059, P = 0.020) between CRP and LAA stroke.

CONCLUSIONS

MR analysis provides evidence for a potential causal relationship between CRP and an increased risk of LAA stroke.

摘要

目的

本研究旨在探讨 C 反应蛋白（CRP）与大动脉粥样硬化（LAA）所致缺血性脑卒中之间的关联。

方法

采用两样本 Mendelian Randomization（MR）分析方法，包括逆方差加权（Inverse Variance Weighting，IVW）、MR-Egger 回归、加权中位数（Weighted Median，WM）、简单模式（Simple Mode）和加权模式（Weighted Mode）。CRP 暴露数据来源于欧洲血统个体全基因组关联研究（genome-wide association studies，GWAS）汇总的汇总统计数据（n = 343524；英国生物银行）。卒中数据作为结局，特定亚组（病例 = 40585，对照 = 406111）的数据集详情。

结果

在 CRP GWAS 数据集中，选择单核苷酸多态性（single nucleotide polymorphisms，SNPs）作为工具变量（instrumental variables，IVs），结果显示与 CRP 呈全基因组显著关联，并与 CRP 呈因果关系，特别是与 LAA 卒中相关。IVW 表明 CRP 与 LAA 卒中之间存在稳健的因果关系（Beta = 0.151，SE = 0.055，P = 0.006）。WM 方法支持这种关系（Beta = 0.176，SE = 0.082，P = 0.033）。然而，MR-Egger 回归提示可能不存在因果关系（Beta = 0.098，SE = 0.077，P = 0.206），水平多效性的影响很小（截距 = 0.0029；P = 0.317）。简单模式未发现显著关联（Beta = 0.046，SE = 0.217，P = 0.834），而加权模式则显示 CRP 与 LAA 卒中之间存在显著的因果关联（Beta = 0.138，SE = 0.059，P = 0.020）。