Exploring the impact of inflammatory cytokines on alcoholic liver disease: a Mendelian randomization study with bioinformatics insights into potential biological mechanisms.

IF 2.7 3区 医学 Q2 PSYCHOLOGY, CLINICAL American Journal of Drug and Alcohol Abuse Pub Date : 2024-09-25 DOI:10.1080/00952990.2024.2402569
Zhitao Chen, Chenchen Ding, Kailei Chen, Chicheng Lu, Qiyong Li
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Abstract

Background: Alcoholic liver disease (ALD) significantly contributes to global morbidity and mortality. The role of inflammatory cytokines in alcohol-induced liver injury is pivotal yet not fully elucidated.Objectives: To establish a causal link between inflammatory cytokines and ALD using a Mendelian Randomization (MR) framework.Methods: This MR study utilized genome-wide significant variants as instrumental variables (IVs) for assessing the relationship between inflammatory cytokines and ALD risk, focusing on individuals of European descent. The approach was supported by comprehensive sensitivity analyses and augmented by bioinformatics tools including differential gene expression, protein-protein interactions (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and analysis of immune cell infiltration.Results: Our findings reveal that increased levels of stem cell growth factor beta (SCGF-β, beta = 0.141, p = .032) and interleukin-7 (IL-7, beta = 0.311, p = .002) are associated with heightened ALD risk, whereas higher levels of macrophage inflammatory protein-1α (MIP-1α, beta = -0.396, p = .004) and basic fibroblast growth factor (bFGF, beta = -0.628, p = .008) are linked to reduced risk. The sensitivity analyses support these robust causal relationships. Bioinformatics analyses around inflammatory cytokine-associated SNP loci suggest multiple pathways through which cytokines influence ALD.Conclusion: The genetic evidence from this study convincingly demonstrates that certain inflammatory cytokines play directional roles in ALD pathogenesis. These findings provide insights into the complex biological pathways involved and underscore the potential for developing targeted therapies that modulate these inflammatory responses, ultimately improving clinical outcomes for ALD patients.

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探索炎症细胞因子对酒精性肝病的影响:一项孟德尔随机化研究与潜在生物机制的生物信息学见解。
背景:酒精性肝病(ALD)是导致全球发病率和死亡率的重要原因。炎性细胞因子在酒精诱导的肝损伤中的作用至关重要,但尚未完全阐明:利用孟德尔随机化(MR)框架建立炎性细胞因子与 ALD 之间的因果联系:这项MR研究利用全基因组重大变异作为工具变量(IV),评估炎性细胞因子与ALD风险之间的关系,重点关注欧洲后裔。该方法得到了综合敏感性分析的支持,并得到了生物信息学工具的辅助,包括差异基因表达、蛋白质-蛋白质相互作用(PPI)、基因本体(GO)、京都基因和基因组百科全书(KEGG)富集分析以及免疫细胞浸润分析:我们的研究结果表明,干细胞生长因子β(SCGF-β,β=0.141,p=0.032)和白细胞介素-7(IL-7,β=0.311,p=0.002)水平升高与ALD风险升高有关,而巨噬细胞炎症蛋白-1α(MIP-1α,β=-0.396,p=0.004)和碱性成纤维细胞生长因子(bFGF,β=-0.628,p=0.008)水平升高与风险降低有关。敏感性分析支持这些稳健的因果关系。围绕炎性细胞因子相关 SNP 位点的生物信息学分析表明,细胞因子通过多种途径影响 ALD:本研究的遗传学证据令人信服地表明,某些炎性细胞因子在 ALD 发病机制中起着定向作用。这些发现深入揭示了所涉及的复杂生物通路,并强调了开发调节这些炎症反应的靶向疗法的潜力,从而最终改善 ALD 患者的临床预后。
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来源期刊
CiteScore
4.70
自引率
3.70%
发文量
68
期刊介绍: The American Journal of Drug and Alcohol Abuse (AJDAA) is an international journal published six times per year and provides an important and stimulating venue for the exchange of ideas between the researchers working in diverse areas, including public policy, epidemiology, neurobiology, and the treatment of addictive disorders. AJDAA includes a wide range of translational research, covering preclinical and clinical aspects of the field. AJDAA covers these topics with focused data presentations and authoritative reviews of timely developments in our field. Manuscripts exploring addictions other than substance use disorders are encouraged. Reviews and Perspectives of emerging fields are given priority consideration. Areas of particular interest include: public health policy; novel research methodologies; human and animal pharmacology; human translational studies, including neuroimaging; pharmacological and behavioral treatments; new modalities of care; molecular and family genetic studies; medicinal use of substances traditionally considered substances of abuse.
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