Druggable genome-wide Mendelian randomization identifies therapeutic targets for metabolic dysfunction-associated steatotic liver disease
Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) affects > 25% of the global population, potentially leading to severe hepatic and extrahepatic complications, including metabolic dysfunction-associated steatohepatitis. Given that the pathophysiology of MASLD is...
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BMC
2025-03-01
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| Series: | Lipids in Health and Disease |
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| Online Access: | https://doi.org/10.1186/s12944-025-02515-8 |
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| author | Xiaohui Ma Li Ding Shuo Li Yu Fan Xin Wang Yitong Han Hengjie Yuan Longhao Sun Qing He Ming Liu |
| author_facet | Xiaohui Ma Li Ding Shuo Li Yu Fan Xin Wang Yitong Han Hengjie Yuan Longhao Sun Qing He Ming Liu |
| author_sort | Xiaohui Ma |
| collection | DOAJ |
| description | Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) affects > 25% of the global population, potentially leading to severe hepatic and extrahepatic complications, including metabolic dysfunction-associated steatohepatitis. Given that the pathophysiology of MASLD is incompletely understood, identifying therapeutic targets and optimizing treatment strategies are crucial for addressing this severe condition. Methods Mendelian randomization (MR) analysis was conducted using two genome-wide association study datasets: a European meta-analysis (8,434 cases; 770,180 controls) and an additional study (3,954 cases; 355,942 controls), identifying therapeutic targets for MASLD. Of 4302 drug-target genes, 2,664 genetic instrument variables were derived from cis-expression quantitative trait loci (cis-eQTLs). Colocalization analyses assessed shared causal variants between MASLD-associated single nucleotide polymorphisms and eQTLs. Using the drug target gene cis-eQTL of liver tissue from the genotype-tissue expression project, we performed MR and summary MR to validate the significance of the gene results of the blood eQTL MR. RNA-sequencing data from liver biopsies were validated using immunohistochemistry and quantitative polymerase chain reaction (qPCR) tests to confirm gene expression findings. Result MR analysis across both datasets identified significant MR associations between MASLD and two drug targets—milk fat globule-EGF factor 8 (MFGE8) (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.85–0.94; P = 2.15 × 10−6) and cluster of differentiation 33 (CD33) (OR 1.17, 95% CI 1.10–1.25; P = 1.39 × 10−6). Both targets exhibited strong colocalization with MASLD. Genetic manipulation indicating MFGE8 activation and CD33 inhibition did not increase the risk for other metabolic disorders. RNA-sequencing, qPCR, and immunohistochemistry validation demonstrated consistent differential expressions of MFGE8 and CD33 in MASLD. Conclusion CD33 inhibition can reduce MASLD risk, while MFGE8 activation may offer therapeutic benefits for MASLD treatment. |
| format | Article |
| id | doaj-art-1e77d6ad323945e8a39909d9bcc0ada9 |
| institution | OA Journals |
| issn | 1476-511X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Lipids in Health and Disease |
| spelling | doaj-art-1e77d6ad323945e8a39909d9bcc0ada92025-08-20T02:10:21ZengBMCLipids in Health and Disease1476-511X2025-03-0124111510.1186/s12944-025-02515-8Druggable genome-wide Mendelian randomization identifies therapeutic targets for metabolic dysfunction-associated steatotic liver diseaseXiaohui Ma0Li Ding1Shuo Li2Yu Fan3Xin Wang4Yitong Han5Hengjie Yuan6Longhao Sun7Qing He8Ming Liu9Department of Endocrinology and Metabolism, Tianjin Medical University General HospitalDepartment of Endocrinology and Metabolism, Tianjin Medical University General HospitalDepartment of Endocrinology and Metabolism, Tianjin Medical University General HospitalDepartment of Endocrinology and Metabolism, Tianjin Medical University General HospitalDepartment of Endocrinology and Metabolism, Tianjin Medical University General HospitalDepartment of General Surgery, Tianjin Medical University General HospitalDepartment of Pharmacy, Tianjin Medical University General HospitalDepartment of General Surgery, Tianjin Medical University General HospitalDepartment of Endocrinology and Metabolism, Tianjin Medical University General HospitalDepartment of Endocrinology and Metabolism, Tianjin Medical University General HospitalAbstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) affects > 25% of the global population, potentially leading to severe hepatic and extrahepatic complications, including metabolic dysfunction-associated steatohepatitis. Given that the pathophysiology of MASLD is incompletely understood, identifying therapeutic targets and optimizing treatment strategies are crucial for addressing this severe condition. Methods Mendelian randomization (MR) analysis was conducted using two genome-wide association study datasets: a European meta-analysis (8,434 cases; 770,180 controls) and an additional study (3,954 cases; 355,942 controls), identifying therapeutic targets for MASLD. Of 4302 drug-target genes, 2,664 genetic instrument variables were derived from cis-expression quantitative trait loci (cis-eQTLs). Colocalization analyses assessed shared causal variants between MASLD-associated single nucleotide polymorphisms and eQTLs. Using the drug target gene cis-eQTL of liver tissue from the genotype-tissue expression project, we performed MR and summary MR to validate the significance of the gene results of the blood eQTL MR. RNA-sequencing data from liver biopsies were validated using immunohistochemistry and quantitative polymerase chain reaction (qPCR) tests to confirm gene expression findings. Result MR analysis across both datasets identified significant MR associations between MASLD and two drug targets—milk fat globule-EGF factor 8 (MFGE8) (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.85–0.94; P = 2.15 × 10−6) and cluster of differentiation 33 (CD33) (OR 1.17, 95% CI 1.10–1.25; P = 1.39 × 10−6). Both targets exhibited strong colocalization with MASLD. Genetic manipulation indicating MFGE8 activation and CD33 inhibition did not increase the risk for other metabolic disorders. RNA-sequencing, qPCR, and immunohistochemistry validation demonstrated consistent differential expressions of MFGE8 and CD33 in MASLD. Conclusion CD33 inhibition can reduce MASLD risk, while MFGE8 activation may offer therapeutic benefits for MASLD treatment.https://doi.org/10.1186/s12944-025-02515-8CD33Mendelian randomization analysisMFGE8Non-alcoholic fatty liver diseaseNonalcoholic steatohepatitis |
| spellingShingle | Xiaohui Ma Li Ding Shuo Li Yu Fan Xin Wang Yitong Han Hengjie Yuan Longhao Sun Qing He Ming Liu Druggable genome-wide Mendelian randomization identifies therapeutic targets for metabolic dysfunction-associated steatotic liver disease Lipids in Health and Disease CD33 Mendelian randomization analysis MFGE8 Non-alcoholic fatty liver disease Nonalcoholic steatohepatitis |
| title | Druggable genome-wide Mendelian randomization identifies therapeutic targets for metabolic dysfunction-associated steatotic liver disease |
| title_full | Druggable genome-wide Mendelian randomization identifies therapeutic targets for metabolic dysfunction-associated steatotic liver disease |
| title_fullStr | Druggable genome-wide Mendelian randomization identifies therapeutic targets for metabolic dysfunction-associated steatotic liver disease |
| title_full_unstemmed | Druggable genome-wide Mendelian randomization identifies therapeutic targets for metabolic dysfunction-associated steatotic liver disease |
| title_short | Druggable genome-wide Mendelian randomization identifies therapeutic targets for metabolic dysfunction-associated steatotic liver disease |
| title_sort | druggable genome wide mendelian randomization identifies therapeutic targets for metabolic dysfunction associated steatotic liver disease |
| topic | CD33 Mendelian randomization analysis MFGE8 Non-alcoholic fatty liver disease Nonalcoholic steatohepatitis |
| url | https://doi.org/10.1186/s12944-025-02515-8 |
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