评估炎症相关基因对心肌炎的因果效应：孟德尔随机研究

IF 3.2 2区医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS

ESC Heart Failure Pub Date : 2024-09-17 DOI:10.1002/ehf2.15064

Huazhen Xiao, Hongkui Chen, Wenjia Liang, Yucheng Liu, Kaiyang Lin, Yansong Guo

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Five algorithms [MR‐Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode regression] were employed for the MR analysis, with IVW as the primary method, and sensitivity analysis was conducted. Subcellular localization and protein–protein interaction (PPI) network analyses were performed for selected biomarkers. Results were verified in ebi‐a‐GCST90018882 (24 180 570 SNPs, 633 cases vs. 427 278 controls) and finn‐b‐I9 MYOCARD EXNONE (16 380 466 SNPs, 829 cases vs. 217 963 controls) to enhance reliability.ResultsIRF7 and ADORA2B were shown to be two exposure factors after screening. Univariable MR (UVMR) analysis revealed that IRF7 was a risk factor for myocarditis [IVW: odd ratio (OR) = 1.041, 95% confidence interval (CI) = 1.018–1.955, P = 0.039], while ADORA2B was a protective factors for myocarditis (IVW: OR = 0.799, 95% CI = 0.640–0.997, P = 0.047). Sensitivity analysis confirmed the robustness of these findings. 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引用次数: 0

摘要

目的已有证据表明，炎症与心肌炎的发生有重要联系。本研究旨在调查炎症相关基因（IRGs）与心肌炎之间的因果关系。方法与结果本研究利用基因组富集分析和整合流行病学单位开放式全基因组关联研究（IEU OpenGWAS）数据库中的数据集调查了 167 个 IRGs 与心肌炎之间的因果关系。GWAS 数据（finn-b-I9 MYOCARD）包含来自 117 755 个心肌炎样本的单核苷酸多态性（SNPs）数据（16 379 455 SNPs，829 个病例与 116 926 个对照）。MR 分析采用了五种算法[MR-Egger、加权中位数、逆方差加权（IVW）、简单模式和加权模式回归]，其中 IVW 为主要方法，并进行了敏感性分析。对选定的生物标记物进行了亚细胞定位和蛋白-蛋白相互作用（PPI）网络分析。结果在 ebi-a-GCST90018882（24 180 570 SNPs，633 例病例与 427 278 例对照）和 finn-b-I9 MYOCARD EXNONE（16 380 466 SNPs，829 例病例与 217 963 例对照）中得到验证，以提高可靠性。单变量磁共振（UVMR）分析显示，IRF7是心肌炎的危险因素[IVW：奇数比（OR）= 1.041，95% 置信区间（CI）= 1.018-1.955，P = 0.039]，而ADORA2B是心肌炎的保护因素（IVW：OR = 0.799，95% CI = 0.640-0.997，P = 0.047）。敏感性分析证实了这些结果的稳健性。多变量磁共振（MVMR）分析进一步证明了 ADORA2B 在预防心肌炎中的直接因果作用。亚细胞定位分析表明，这两个基因主要在细胞质表达，线粒体表达有限。PPI分析结果显示，有20个基因被预测与IRF7的功能有关，如对I型干扰素的反应、模式识别受体信号通路和toll样受体信号通路。结论研究结果表明，IRGs（IRF7和ADORA2B）与心肌炎之间存在因果关系，这为今后的研究和心肌炎的治疗提供了重要的参考和指导。

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Assessing the causal effect of inflammation‐related genes on myocarditis: A Mendelian randomization study

AimsPrior evidence has shown a significant link between inflammation and the development of myocarditis. This study aimed to investigate the causal relationship between inflammation‐related genes (IRGs) and myocarditis.Methods and resultsIn this study, the causal relationship between 167 IRGs and myocarditis were investigated using datasets from the Gene Set Enrichment Analysis and Integrative Epidemiology Unit open genome‐wide association study (IEU OpenGWAS) databases. The GWAS data (finn‐b‐I9 MYOCARD) contained single nucleotide polymorphisms (SNPs) data from 117 755 myocarditis samples (16 379 455 SNPs, 829 cases vs. 116 926 controls). Five algorithms [MR‐Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode regression] were employed for the MR analysis, with IVW as the primary method, and sensitivity analysis was conducted. Subcellular localization and protein–protein interaction (PPI) network analyses were performed for selected biomarkers. Results were verified in ebi‐a‐GCST90018882 (24 180 570 SNPs, 633 cases vs. 427 278 controls) and finn‐b‐I9 MYOCARD EXNONE (16 380 466 SNPs, 829 cases vs. 217 963 controls) to enhance reliability.ResultsIRF7 and ADORA2B were shown to be two exposure factors after screening. Univariable MR (UVMR) analysis revealed that IRF7 was a risk factor for myocarditis [IVW: odd ratio (OR) = 1.041, 95% confidence interval (CI) = 1.018–1.955, P = 0.039], while ADORA2B was a protective factors for myocarditis (IVW: OR = 0.799, 95% CI = 0.640–0.997, P = 0.047). Sensitivity analysis confirmed the robustness of these findings. Multivariable MR (MVMR) analysis further demonstrated a direct causal role of ADORA2B in preventing myocarditis. Subcellular localization analysis indicated predominant cytoplasmic expression and limited mitochondrial expression for both genes. The results of PPI analysis showed that 20 genes were predicted to be associated with IRF7 function, such as response to type I interferon, pattern recognition receptor signalling pathway, and toll‐like receptor signalling pathway. The results in finn‐b‐I9 MYOCARD EXNONE were consistent with MR analysis.ConclusionsThe findings indicated there was a causal connection between IRGs (IRF7 and ADORA2B) and myocarditis, which offered a crucial point of reference and guidance for future studies and myocarditis treatment.

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来源期刊

ESC Heart Failure Medicine-Cardiology and Cardiovascular Medicine

CiteScore

7.00

自引率

7.90%

发文量

461

审稿时长

12 weeks

期刊介绍： ESC Heart Failure is the open access journal of the Heart Failure Association of the European Society of Cardiology dedicated to the advancement of knowledge in the field of heart failure. The journal aims to improve the understanding, prevention, investigation and treatment of heart failure. Molecular and cellular biology, pathology, physiology, electrophysiology, pharmacology, as well as the clinical, social and population sciences all form part of the discipline that is heart failure. Accordingly, submission of manuscripts on basic, translational, clinical and population sciences is invited. Original contributions on nursing, care of the elderly, primary care, health economics and other specialist fields related to heart failure are also welcome, as are case reports that highlight interesting aspects of heart failure care and treatment.