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Multiomics and Cohort Validation Identified the Metabolic Link Between Hashimoto′s Thyroiditis and Primary Biliary Cholangitis
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DOI：10.1155/humu/3956260.png)
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Abstract
En 中文
Primary biliary cholangitis (PBC) was one of the most prevalent autoimmune liver diseases. Hashimoto′s thyroiditis (HT) represented the most commonly associated thyroid disorder in patients with PBC. Both diseases shared overlapping clinical characteristics, including genetic susceptibility and metabolic disturbances; however, the precise mechanisms underlying their co-occurrence remained unclear. This study utilized a two-sample mediation Mendelian randomization approach leveraging eQTL and GWAS data associated with metabolism. The causal relationship between PBC and HT was systematically investigated. Furthermore, metabolic genes were employed as mediator factors to elucidate the specific roles of mediator molecules in both conditions, leading to the identification of four hub genes. Subsequently, a clinical prediction model and nomogram were developed. The distribution and expression levels of the four hub genes across cell subtypes were characterized through single-cell sequencing analysis. Finally, hub genes were verified in liver biopsy tissues from patients in our own clinical cohort. Our research has demonstrated a causal relationship between HT and PBC. Mediation analysis identified four metabolic genes—CRLS1, ACAA2, SAT2, and HADH—as playing a critical role in this association. Gene Set Enrichment Analysis (GSEA) revealed that the hub genes were primarily enriched in glycolysis, gluconeogenesis, and propionate-related pathways. The machine learning and nomogram exhibited excellent diagnostic performance. Single-cell analysis further indicated that the hub genes were predominantly highly expressed in hepatocytes (Hep0 and Hep3). Through cell communication analysis, hepatocytes exhibited significant interactions with immune cell. The expression of four hub genes was lower in PBC patients with HT, validated in liver tissues from clinical cohort. Our findings underscored the pivotal role of metabolic genes in the progression from HT to PBC based on multiomics analysis.
Keywords:
clinical cohort study
GWAS
Hashimoto′s thyroiditis
machine learning
primary biliary cholangitis
single-cell analysis
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