Clin Mol Hepatol.
2024 Jan;30(1):80-97. 10.3350/cmh.2023.0343.
Protein-centric omics analysis reveals circulating complements linked to non-viral liver diseases as potential therapeutic targets
- Shi Y1,2,3,4,5,
- Dong H1,2,3,4,5,
- Sun S2,3,4,5,6,
- Wu X8
- Fang J9
- Zhao J2,3,4,5,6,
- Han J2,3,4,5,6,
- Li Z2,3,4,5,6,
- Wu H2,3,4,5,6,
- Liu L1,2,3,4,5,
- Wu W2,3,4,5,6,
- Tian Y1,2,3,4,5,
- Yuan G
11 - Fan X2,3,4,5,6,
- Xu C1,2,3,4,5,
- Affiliations
-
- 1Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- 2Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- 3Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- 4Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- 5“Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- 6Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- 7Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- 8Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
- 9Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- 10Clinical Medical College, Ningxia Medical University, Yinchuan, Ningxia, China
- 11Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- KMID: 2549385
- DOI: http://doi.org/10.3350/cmh.2023.0343
Abstract
- Background/Aims
To evaluate the causal correlation between complement components and non-viral liver diseases and their potential use as druggable targets.
Methods
We conducted Mendelian randomization (MR) to assess the causal role of circulating complements in the risk of non-viral liver diseases. A complement-centric protein interaction network was constructed to explore biological functions and identify potential therapeutic options.
Results
In the MR analysis, genetically predicted levels of complement C1q C chain (C1QC) were positively associated with the risk of autoimmune hepatitis (odds ratio 1.125, 95% confidence interval 1.018–1.244), while complement factor H-related protein 5 (CFHR5) was positively associated with the risk of primary sclerosing cholangitis (PSC;1.193, 1.048– 1.357). On the other hand, CFHR1 (0.621, 0.497–0.776) and CFHR2 (0.824, 0.703–0.965) were inversely associated with the risk of alcohol-related cirrhosis. There were also significant inverse associations between C8 gamma chain (C8G) and PSC (0.832, 0.707–0.979), as well as the risk of metabolic dysfunction-associated steatotic liver disease (1.167, 1.036–1.314). Additionally, C1S (0.111, 0.018–0.672), C7 (1.631, 1.190–2.236), and CFHR2 (1.279, 1.059–1.546) were significantly associated with the risk of hepatocellular carcinoma. Proteins from the complement regulatory networks and various liver diseaserelated proteins share common biological processes. Furthermore, potential therapeutic drugs for various liver diseases were identified through drug repurposing based on the complement regulatory network.
Conclusions
Our study suggests that certain complement components, including C1S, C1QC, CFHR1, CFHR2, CFHR5, C7, and C8G, might play a role in non-viral liver diseases and could be potential targets for drug development.
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