Shi Xiang, Zhang Lu, Huang Wei, Li Min, Chen Yuyan, Hu Yilin, Lu Cuihua, Xu Chenzhou, Liu Zhaoxiu
Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu, China.
Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
Br J Hosp Med (Lond). 2025 Jul 25;86(7):1-19. doi: 10.12968/hmed.2025.0067. Epub 2025 Jul 22.
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. 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. 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. 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.
胃食管反流病（GERD）是一种广泛存在的食管胃上部疾病，其生物学机制尚未完全明确。新出现的证据支持GERD与代谢标志物之间存在复杂联系。因此，孟德尔随机化（MR）这种创新性的基因组学方法被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。采用两样本MR框架来检验循环代谢物与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。主要因果推断使用逆方差加权（IVW）方法，并辅以补充和敏感性分析以验证研究结果的可靠性。分析框架纳入了多种验证方法，包括重复验证、荟萃分析、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。采用系统途径分析来阐明相关途径和潜在的疾病机制。IVW分析确定了血清代谢物与GERD之间的32种因果关联。通过后续的敏感性分析，确定了13种代谢物与GERD之间存在稳健的因果联系。通过应用多种先进方法，如重复验证、荟萃分析、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，证实了两种代谢物，即肾上腺酸（22:4n6）和2 - 棕榈酰甘油磷酸胆碱，对GERD具有稳定且独立的影响。途径分析表明，色氨酸代谢、胆汁酸生物合成和肉碱合成等三种代谢途径与GERD存在显著关联。本研究使用综合基因组学和代谢组学方法，提供了证据支持两种血清代谢物和三种代谢途径对GERD的因果影响，突出了这些代谢物作为早期筛查、诊断和靶向治疗策略的有前景生物标志物的潜力。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方面的重要性。
