Mendelian randomization study on causal association of TEF and circadian rhythm with pulmonary arterial hypertension.

IF 5.8 2区 医学 Q1 Medicine Respiratory Research Pub Date : 2024-08-07 DOI:10.1186/s12931-024-02934-8
Dandan Chen, Qi Jin, Lifan Yang, Xiaochun Zhang, Mingfei Li, Lei Zhang, Wenzhi Pan, Daxin Zhou, Junbo Ge, Lihua Guan
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Abstract

Background: Previous research has revealed the potential impact of circadian rhythms on pulmonary diseases; however, the connection between circadian rhythm-associated Thyrotroph Embryonic Factor (TEF) and Pulmonary Arterial Hypertension (PAH) remains unclear. We aim to assess the genetic causal relationship between TEF and PAH by utilizing two sets of genetic instrumental variables (IV) and publicly available Pulmonary Arterial Hypertension Genome-Wide Association Studies (GWAS).

Methods: Total of 23 independent TEF genetic IVs from recent MR reports and PAH GWAS including 162,962 European individuals were used to perform this two-sample MR study. Gain- and loss-of-function experiments were used to demonstrate the role of TEF in PAH.

Results: Our analysis revealed that as TEF levels increased genetically, there was a corresponding increase in the risk of PAH, as evidenced by IVW (OR = 1.233, 95% CI: 1.054-1.441; P = 0.00871) and weighted median (OR = 1.292, 95% CI for OR: 1.064-1.568; P = 0.00964) methods. Additionally, the up-regulation of TEF expression was associated with a significantly higher likelihood of abnormal circadian rhythm (IVW: P = 0.0024733, β = 0.05239). However, we did not observe a significant positive correlation between circadian rhythm and PAH (IVW: P = 0.3454942, β = 1.4980398). In addition, our in vitro experiments demonstrated that TEF is significantly overexpressed in pulmonary artery smooth muscle cells (PASMCs). And overexpression of TEF promotes PASMC viability and migratory capacity, as well as upregulates the levels of inflammatory cytokines.

Conclusion: Our analysis suggests a causal relationship between genetically increased TEF levels and an elevated risk of both PAH and abnormal circadian rhythm. Consequently, higher TEF levels may represent a risk factor for individuals with PAH.

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关于 TEF 和昼夜节律与肺动脉高压因果关系的孟德尔随机研究。
背景:以往的研究揭示了昼夜节律对肺部疾病的潜在影响;然而,昼夜节律相关的甲状腺胚胎因子(TEF)与肺动脉高压(PAH)之间的联系仍不清楚。我们旨在利用两组遗传工具变量(IV)和公开的肺动脉高压全基因组关联研究(GWAS)来评估TEF与PAH之间的遗传因果关系:在这项双样本 MR 研究中,使用了最近 MR 报告和 PAH GWAS(包括 162 962 名欧洲个体)中的 23 个独立 TEF 遗传 IV。结果:我们的分析表明,随着 TEF 水平的升高,PAH 中的 TEF 基因水平也随之升高:我们的分析表明,随着 TEF 水平的遗传增加,PAH 的风险也相应增加,IVW(OR = 1.233,95% CI:1.054-1.441;P = 0.00871)和加权中位数(OR = 1.292,95% CI 为 OR:1.064-1.568;P = 0.00964)方法证明了这一点。此外,TEF表达的上调与昼夜节律异常的可能性显著增加有关(IVW:P = 0.0024733,β = 0.05239)。然而,我们并未观察到昼夜节律与 PAH 之间存在明显的正相关性(IVW:P = 0.3454942,β = 1.4980398)。此外,我们的体外实验表明,TEF 在肺动脉平滑肌细胞(PASMCs)中明显过表达。结论:我们的分析表明,TEF 在肺动脉平滑肌细胞(PASMC)中的过度表达与肺动脉平滑肌细胞的活力和迁移能力有关:我们的分析表明,遗传性 TEF 水平升高与 PAH 和昼夜节律异常风险升高之间存在因果关系。因此,较高的 TEF 水平可能是 PAH 患者的一个风险因素。
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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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