Cai Xueyao, Li Weidong, Shi Wenjun, Liu Can, Cai Yuchen, Zhou Jianda
Department of Plastic Surgery The Third Xiangya Hospital of Central South University Changsha Hunan China.
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China.
Food Sci Nutr. 2025 Oct 31;13(11):e71094. doi: 10.1002/fsn3.71094. eCollection 2025 Nov.
The contribution of circulating micronutrients to ulcer susceptibility remains poorly defined across anatomical sites. In this study, we constructed a systematic trace element-ulcer map by integrating genetic-instrumented inference, pleiotropy-aware modeling, and heterogeneity-sensitive clustering. Summary-level data were obtained from large-scale genome-wide association studies (GWAS) encompassing 10 circulating micronutrients (calcium, iron, zinc, copper, magnesium, selenium, carotene, vitamin B12, vitamin C, and vitamin D) and nine ulcer phenotypes (corneal ulcer, recurrent oral aphthae, esophageal ulcer, gastric ulcer, duodenal ulcer, vaginal/vulvar ulcer, decubitus ulcer, lower limb ulcer, and chronic skin ulcer), covering more than 3 million individuals of European ancestry. Our two-sample Mendelian randomization (MR) analysis identified genetically elevated zinc levels as a risk factor for gastric (OR: 1.141, 95% CI: 1.060-1.228, = 4.57 × 10) and esophageal ulcers, but inversely associated with vaginal/vulvar ulcer risk. Protective effects were observed for iron with gastric ulcers and calcium with duodenal ulcers. Carotene and magnesium were nominally associated with increased risk of oral aphthae and vaginal ulcers, respectively. To refine these associations, we applied Causal Analysis Using Summary Effect estimates (CAUSE) and MR-Clust. While CAUSE did not confirm robust putative causal relationships in most pairs, MR-Clust uncovered three distinct SNP clusters in the vitamin C-corneal ulcer pair, indicating potential mechanistic heterogeneity. These pleiotropy-aware and cluster-based approaches enhanced the interpretability of borderline signals and revealed genetic heterogeneity beyond mean-effect estimates. Collectively, this study offers a panoramic view of trace element-ulcer relationships and prioritizes zinc as a key candidate for further mechanistic exploration in gastric ulcer pathogenesis. Our integrative framework may serve as a foundation for future etiological and nutritional intervention studies.
循环中的微量营养素对不同解剖部位溃疡易感性的影响仍未明确界定。在本研究中，我们通过整合基因工具推断、多效性感知建模和异质性敏感聚类构建了一个系统的微量元素 - 溃疡图谱。汇总水平的数据来自大规模全基因组关联研究（GWAS），涵盖10种循环微量营养素（钙、铁、锌、铜、镁、硒、胡萝卜素、维生素B12、维生素C和维生素D）和9种溃疡表型（角膜溃疡、复发性口腔溃疡、食管溃疡、胃溃疡、十二指肠溃疡、阴道/外阴溃疡、压疮溃疡、下肢溃疡和慢性皮肤溃疡），涉及超过300万欧洲血统个体。我们的两样本孟德尔随机化（MR）分析确定，基因决定的锌水平升高是胃溃疡（比值比：1.141，95%置信区间：1.060 - 1.228，P = 4.57×10⁻⁴）和食管溃疡的危险因素，但与阴道/外阴溃疡风险呈负相关。观察到铁对胃溃疡有保护作用，钙对十二指肠溃疡有保护作用。胡萝卜素和镁分别与口腔溃疡和阴道溃疡风险增加名义上相关。为了细化这些关联，我们应用了基于汇总效应估计的因果分析（CAUSE）和MR - Clust方法。虽然CAUSE在大多数配对中未确认强有力的因果关系，但MR - Clust在维生素C - 角膜溃疡配对中发现了三个不同的单核苷酸多态性（SNP）簇，表明潜在的机制异质性。这些多效性感知和基于聚类的方法增强了临界信号的可解释性，并揭示了超出平均效应估计的基因异质性。总体而言，本研究提供了微量元素与溃疡关系的全景图，并将锌确定为胃溃疡发病机制中进一步进行机制探索的关键候选因素。我们的综合框架可为未来的病因学和营养干预研究奠定基础。
