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Identification of key genes associated with butyrate metabolism in keratoconus through Mendelian randomization and
1Hospital of Chengdu University of Traditional Chinese Medicine, China; School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, China.
Background:
Keratoconus (KC) is a degenerative corneal disease with a complex etiology that severely affects vision. Butyrate is a saturated short-chain fatty acid with anti-inflammatory properties. Accumulating evidence underscores a significant role for inflammation in KC pathogenesis. However, the specific role of butyrate metabolism in KC remained unclear. This study aimed to identify key genes associated with butyrate-related regulatory pathways in KC.
Methods:
The KC-related dataset GSE77938, GSE151631, genome-wide association studies (GWAS) data for KC (finn-b-H7_CORNEALDEFORM) and butyrate metabolism-related genes (BMRGs) were from public databases. Firstly, differentially expressed genes (DEGs) between KC and control samples were intersected with BMRGs and key module genes related to KC to identify candidate genes. Subsequently, key genes with causal links to KC were identified by integrating Mendelian randomization, machine learning, and expression validation analyses. Following this, based on key genes, the function enrichment, immune infiltration, molecular regulatory network, drugs prediction and molecular docking were performed, respectively. Finally, the key genes expression was validated clinically using reverse transcription-quantitative polymerase chain reaction (RT-PCR).
Results:
A total of 3 key genes (CCN2, GATA2 and ZFP36L1) were obtained. Enrichment analysis showed that 3 key genes were co-enriched in 53 pathways, like "cytokine and cytokine receptor interaction", "ribosome". Significant differences in 25 immune cells, like activated mast cells and activated CD4 T cells were observed between the KC and control groups. Subsequently, the hsa-mir-124-3p involved with CCN2 and ZFP36L1 and hsa-mir-27a-3p interacted with GATA2 and ZFP36L1. 1 lncRNAs (LINC01355) interacted with 7 miRNAs, like hsa-mir-181a-5p. Furthermore, drug prediction analysis and molecular docking pointed that acridine may interact with CCN2.
Conclusion:
This study identified 3 key genes (CCN2, GATA2 and ZFP36L1), which provide new insights into the potential role of butyrate-associated regulatory mechanisms in KC.
