遗传分析确定与胃食管反流病风险相关的人类血清代谢物:孟德尔随机研究

IF 1.8 4区 医学 Q3 MEDICINE, GENERAL & INTERNAL
British journal of hospital medicine Pub Date : 2025-07-25 Epub Date: 2025-07-22 DOI:10.12968/hmed.2025.0067
Xiang Shi, Lu Zhang, Wei Huang, Min Li, Yuyan Chen, Yilin Hu, Cuihua Lu, Chenzhou Xu, Zhaoxiu Liu
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引用次数: 0

摘要

目的/背景胃食管反流病(GERD)是一种广泛存在的上食管胃疾病,其生物学机制尚不完全清楚。新出现的证据支持胃食管反流与代谢标志物之间的复杂联系。因此,孟德尔随机化(MR)是一种创新的基因组方法,用于评估血清代谢物对GERD的因果影响,旨在识别新的生物标志物并阐明潜在的代谢途径。方法采用双样本MR框架研究循环代谢物与GERD之间的因果关系。486种代谢性状的遗传工具来自一项全面的代谢组学全基因组关联研究(GWAS),疾病结局数据来自GERD队列。采用逆方差加权(IVW)方法进行主要因果推断,并辅以互补分析和敏感性分析来验证研究结果的可靠性。分析框架采用了多种验证方法,包括复制、meta分析、连锁不平衡评分回归、共定位分析、反向MR分析和多变量MR分析。采用系统的途径分析来阐明相关途径和潜在的疾病机制。结果IVW分析确定了血清代谢物与GERD之间的32种因果关系。通过随后的敏感分析,确定了13种代谢物与GERD之间的牢固因果关系。通过应用复制、meta分析、连锁不平衡评分回归、共定位分析、反向MR分析和多变量MR分析等先进方法,证实肾上腺素(22:4n6)和2-棕榈酰甘油磷酸胆碱两种代谢物对胃食管反流有稳定且独立的影响。途径分析显示,色氨酸代谢、胆汁酸生物合成和肉碱合成这三条代谢途径与胃食管反流具有显著相关性。利用整合基因组学和代谢组学方法,本研究提供了支持两种血清代谢物和三种代谢途径对GERD的因果影响的证据,强调了这些代谢物作为早期筛查、诊断和靶向治疗策略的有希望的生物标志物的潜力。此外,这些发现强调了整合基因组学和代谢组学在理解疾病病理生理学中的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Genetic Analyses Identify Human Serum Metabolites Associated With Risk of Gastroesophageal Reflux Disease: A Mendelian Randomization Study.

Aims/Background Gastroesophageal reflux disease (GERD) is a widespread upper esophagogastric disease with incompletely understood biological mechanisms. Emerging evidence supports a complex link between GERD and metabolic markers. Therefore, Mendelian randomization (MR), an innovative genomic approach, was used to evaluate the causal impacts of serum metabolites on GERD, aiming to identify novel biomarkers and elucidate underlying metabolic pathways. Methods A two-sample MR framework was employed to examine causal relationships between circulating metabolites and GERD. Genetic instruments for 486 metabolic traits were derived from a comprehensive metabolomics genome-wide association study (GWAS), with disease outcome data from GERD cohorts. Primary causal inference was conducted using the inverse variance weighted (IVW) method, supported by complementary and sensitivity analyses to validate the reliability of the findings. The analytical framework incorporated multiple validation approaches, including replication, meta-analysis, linkage disequilibrium score regression, colocalization analysis, reverse MR analysis, and multivariable MR analysis. Systematic pathway analysis was employed to elucidate associated pathways and underlying disease mechanisms. Results The IVW analysis identified 32 causal associations between serum metabolites and GERD. Through subsequent sensitive analyses, robust causal links were identified between 13 metabolites and GERD. By applying several advanced approaches, such as replication, meta-analysis, linkage disequilibrium score regression, colocalization analyses, reverse MR analysis, and multivariable MR analysis, two metabolites, adrenate (22:4n6) and 2-palmitoylglycerophosphocholine, were confirmed to have stable and independent impacts on GERD. Pathway analysis revealed that three metabolic pathways, such as tryptophan metabolism, bile acid biosynthesis, and carnitine synthesis, exhibited significant association with GERD. Conclusion Using integrative genomics and metabolomics approaches, this study provides evidence supporting the causal influence of two serum metabolites and three metabolic pathways on GERD, highlighting the potential of these metabolites as promising biomarkers for early screening, diagnosis, and targeted treatment strategies. Moreover, these findings underscore the significance of integrating genomics and metabolomics in understanding disease pathophysiology.

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来源期刊
British journal of hospital medicine
British journal of hospital medicine 医学-医学:内科
CiteScore
1.50
自引率
0.00%
发文量
176
审稿时长
4-8 weeks
期刊介绍: British Journal of Hospital Medicine was established in 1966, and is still true to its origins: a monthly, peer-reviewed, multidisciplinary review journal for hospital doctors and doctors in training. The journal publishes an authoritative mix of clinical reviews, education and training updates, quality improvement projects and case reports, and book reviews from recognized leaders in the profession. The Core Training for Doctors section provides clinical information in an easily accessible format for doctors in training. British Journal of Hospital Medicine is an invaluable resource for hospital doctors at all stages of their career. The journal is indexed on Medline, CINAHL, the Sociedad Iberoamericana de Información Científica and Scopus.
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