Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
BMJ Open Gastroenterol. 2024 Aug 28;11(1):e001417. doi: 10.1136/bmjgast-2024-001417.
Gallstone disease affects ≥40 million people in the USA and accounts for health costs of ≥$4 billion a year. Risk factors such as obesity and metabolic syndrome are well established. However, data are limited on relevant metabolomic alterations that could offer mechanistic and predictive insights into gallstone disease. This study prospectively identifies and externally validates circulating prediagnostic metabolites associated with incident gallstone disease.
Female participants in Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II) who were free of known gallstones (N=9960) were prospectively followed up after baseline metabolomic profiling with liquid chromatography-tandem mass spectrometry. Multivariable logistic regression and enrichment analysis were used to identify metabolites and metabolite groups associated with incident gallstone disease at P<0.05. Findings were validated in 1866 female participants in the Women's Health Initiative and a comparative analysis was performed with 2178 male participants in the Health Professionals Follow-up Study.
After multivariate adjustment for lifestyle and putative risk factors, we identified and externally validated 17 metabolites associated with incident gallstone disease in women-nine triacylglycerols (TAGs) and diacylglycerols (DAGs) were positively associated, while eight plasmalogens and cholesterol ester (CE) were negatively associated. Enrichment analysis in male and female cohorts revealed positive class associations with DAGs, TAGs (≤56 carbon atoms and ≤3 double bonds) and de novo TAG biosynthesis pathways, as well as inverse associations with CEs.
This study highlights several metabolites (TAGs, DAGs, plasmalogens and CE) that could be implicated in the aetiopathogenesis of gallstone disease and serve as clinically relevant markers.
胆石病影响美国超过 4000 万人，每年造成的健康成本超过 40 亿美元。肥胖和代谢综合征等风险因素已得到充分证实。然而，关于可能为胆石病提供机制和预测性见解的相关代谢组学改变的数据有限。本研究前瞻性地确定并验证了与胆石病发病相关的循环预诊断代谢物。
在基线代谢组学特征分析后，无已知胆石症的女性参与者（N=9960）参加了护士健康研究（NHS）和护士健康研究 II（NHS II），并进行了前瞻性随访。使用多变量逻辑回归和富集分析，以确定与胆石病发病相关的代谢物和代谢物组（P<0.05）。在妇女健康倡议中的 1866 名女性参与者中验证了这些发现，并在健康专业人员随访研究中的 2178 名男性参与者中进行了比较分析。
在对生活方式和潜在风险因素进行多变量调整后，我们确定并验证了与女性胆石病发病相关的 17 种代谢物-九种三酰基甘油（TAG）和二酰基甘油（DAG）呈正相关，而八种血浆脂和胆固醇酯（CE）呈负相关。在男性和女性队列中的富集分析显示，DAG、TAG（≤56 个碳原子和≤3 个双键）和从头 TAG 生物合成途径呈正类关联，而 CE 呈负类关联。
本研究强调了几种代谢物（TAG、DAG、血浆脂和 CE）可能与胆石病的发病机制有关，并可作为临床相关标志物。
