GWAS Reveals Distinct Genetic Architecture of Schistosomiasis-Induced Hepatic Fibrosis with DGKG as a Key Mediator
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Abstract Background & Aims Schistosomiasis is a major cause of hepatic fibrosis in endemic regions, yet the host genetic determinants of disease progression remain poorly defined. We aimed to identify genetic drivers and underlying mechanisms of schistosomiasis-induced hepatic fibrosis. Methods We performed a genome-wide association study (GWAS) of 984 Schistosoma japonicum -infected individuals from hyperendemic areas in China followed by multi-omics integration and experimental validation to identify causal genes and fibrogenic pathways. Results Schistosomiasis-associated fibrosis exhibited a genetic architecture distinct from metabolic and viral liver fibrosis, supporting pathogen-specific mechanisms. Eight novel susceptibility loci were identified, including a genome-wide significant signal at 16p13 (rs73575170, P = 3.9 × 10⁻⁸). Integrative mapping linked these loci to 262 genes enriched in liver sinusoidal endothelial cells ( P = 5.84 × 10⁻⁵) and sphingolipid metabolism pathways ( P = 4.19 × 10⁻⁵). Notably, Diacylglycerol kinase gamma ( DGKG , rs6762330, P = 4.37 × 10⁻⁶) emerged as a key candidate, with its expression in peri-granuloma and periportal hepatocytes strongly correlating with fibrosis severity ( r = 0.816). In vivo , Dgkg knockout attenuated hepatic fibrosis and immunopathology while restoring cholesterol homeostasis, whereas Dgkg overexpression exacerbated fibrogenesis and increased TNF-α levels tenfold. Conclusions This study identifies DGKG as a key mediator linking lipid metabolism and immune signaling in schistosomiasis-induced fibrosis, uncovering a pathogen-specific genetic mechanism and providing a potential therapeutic target for infection-associated liver fibrosis. Impact and Implications This study defines a pathogen-specific genetic architecture underlying schistosomiasis-associated hepatic fibrosis, distinguishing it from metabolic and viral fibrotic liver diseases. By integrating GWAS analysis and in vivo functional validation, DGKG is identified as a key regulator linking lipid metabolism and immune-driven fibrogenesis. These findings highlight liver sinusoidal endothelial cells and sphingolipid signaling as critical cellular and molecular contexts for schistosomiasis-associated hepatic fibrosis. Beyond advancing mechanistic understanding of schistosomiasis, this work provides a genetic and functional framework for targeting DGKG -mediated pathways, with potential implications for precision therapies in parasitically mediated liver fibrotic disorders.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- GWAS Reveals Distinct Genetic Architecture of Schistosomiasis-Induced Hepatic Fibrosis with <i>DGKG</i> as a Key Mediator
- Date Crossref
- 24/03/2026
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Sun Yat-sen University Department of Pathology pays non établi dans la noticeUniversité ou école supérieure
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Jiaying University pays non établi dans la noticeUniversité ou école supérieure
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Shenzhen Bay Laboratory pays non établi dans la noticeStructure de recherche
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Jiangsu Institute of Parasitic Diseases pays non établi dans la noticeStructure de recherche
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Abdul Wali Khan University Mardan Zoology Department pays non établi dans la noticeUniversité ou école supérieure
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Hainan General Hospital pays non établi dans la noticeÉtablissement de santé
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Hainan Medical University Hainan General Hospital pays non établi dans la noticeUniversité ou école supérieure
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Stomatology Hospital pays non établi dans la noticeÉtablissement de santé
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Medical College pays non établi dans la noticeUniversité ou école supérieure
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Zhongshan School of Medicine pays non établi dans la noticeUniversité ou école supérieure
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Institute of Systems and Physical Biology pays non établi dans la noticeStructure de recherche
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Jiangxi Provincial Institute of Parasitic Diseases pays non établi dans la noticeStructure de recherche
Department of Pathology — Sun Yat-sen University, Jiaying University et Shenzhen Bay Laboratory, avec 9 autres affiliations.
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