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Lactylation-Related Genes in Ulcerative Colitis: A Multiomics Mendelian Randomization Study for Therapeutic Target
Na An1, Ruiyun Wang2, Huiping Jiao3
1Anorectal Department, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China, sdutcm.edu.cn.
Background:
Ulcerative colitis (UC), a chronic and nonspecific intestinal inflammatory disease, has seen a rising incidence rate worldwide year by year. Its pathogenesis remains incompletely understood. Lactylation modification is closely related to the generation of inflammation. Exploring the pathogenesis of UC from the perspective of lactylation is of great significance for the understanding and treatment of UC.
Method:
Forty-six lactylation genes were retrieved from the literature and intersected with the eQTLGen whole blood cis-eQTL to screen 29 candidate genes. Taking UC (finngen_R12_ULCERNAS, 482,657 participants) in the Finnish database as the outcome, significant eQTLs were selected as instrumental variables. The core genes were identified through multimodel Mendelian randomization with inverse variance weighting and heterogeneity and pleiotropy tests. Subsequently, the causal association was reverified by SMR, and differential expression analysis was performed after batch correction in combination with the GEO dataset. The expression profiles of cell subpopulations were analyzed based on single-cell data (GSE214695). Finally, the UC inflammation model was constructed by LPS-induced colonic epithelial cells, and the expression changes of the target genes were verified and determined by qPCR experiments. Then, the expression of the genes in the UC was re-examined in the spatial transcriptome samples.
Result:
Mendelian randomization identified EP300, LDHC, and STMN1 as causal genes involved in the lactylation mechanism of UC. The GEO dataset shows that EP300 and STMN1 are significantly upregulated in the UC group. Single-cell maps revealed that STMN1 was enriched in B cells, LDHC, and EP300 in endothelial cells. The qPCR experiment and spatial transcriptome sample confirmed that STMN1 was upregulated most significantly.
Conclusion:
STMN1 and EP300 have been identified as causal genes for UC. The expression of STMN1 in UC significantly increased, and it was specifically enriched in B cells and monocytes. Lactic acid modification may participate in the pathogenesis of UC by driving immune imbalance, providing a genetic basis for the development of new diagnostic markers and targeted lactate intervention strategies.
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Diagnostic studies
A colonoscopy is the definitive screening test, distinguishing ulcerative colitis from other colon diseases with similar symptoms. During a colonoscopy test, inflamed mucosa with exudate ulcerations can be observed, and biopsies are taken to determine the histologic characteristics of the colonic...