# A Trace Element–Ulcer Map: Decoding Micronutrient–Ulcer Relationships Through Genetic Architecture and Pleiotropy‐Aware Inference

## TL;DR

This study explores how trace elements like zinc and iron influence ulcer risk using genetic data, identifying zinc as a key factor in gastric ulcers.

## Contribution

The study introduces a genetic framework to map trace element-ulcer relationships, revealing novel associations and heterogeneity in causal mechanisms.

## Key findings

- Genetically elevated zinc levels increase risk for gastric and esophageal ulcers but reduce risk for vaginal/vulvar ulcers.
- Iron and calcium show protective effects for gastric and duodenal ulcers, respectively.
- MR-Clust identified three distinct SNP clusters in the vitamin C-corneal ulcer pair, suggesting mechanistic heterogeneity.

## Abstract

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, p = 4.57 × 10−4) 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.

This study established a genetic correlation between circulating micronutrients and ulcer development, focusing specifically on the impact of circulating zinc on gastric ulcers. Further correlations were identified, such as the association between circulating zinc on esophageal and vaginal/vulvar ulcers, iron on gastric ulcers, magnesium on vaginal/vulvar ulcers, carotene on recurrent oral aphthae, and calcium on duodenal ulcers. While CAUSE did not confirm robust causality in most pairs, MR‐Clust uncovered three distinct SNP clusters in the vitamin C‐corneal ulcer pair, indicating potential mechanistic heterogeneity.