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Published on: April 4, 2018
Identification of an Endoglin Variant Associated With HCV-Related Liver Fibrosis Progression by Next-Generation
Frédégonde About1,2, Stéphanie Bibert3, Emmanuelle Jouanguy1,2
1Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Paris, France.
Insights
Genetic variants in the endoglin gene (ENG) are linked to liver fibrosis in hepatitis C virus (HCV) patients. A specific ENG variant, Thr5Met, increases fibrosis risk, highlighting endoglin
Area of Science:
- Hepatology and Viral Gastroenterology
- Human Genetics and Genomics
- Molecular Biology and Biochemistry
Background:
- Chronic hepatitis C virus (HCV) infection, despite antiviral treatments, poses a significant risk for liver fibrosis.
- Host genetic factors influence fibrosis development, but common variants have shown limited impact.
- Understanding genetic predispositions is crucial for managing HCV-related liver disease.
Purpose of the Study:
- To investigate the role of host genetic factors in the development of liver fibrosis in HCV-infected patients.
- To identify specific genetic variants associated with increased risk of liver fibrosis in HCV infection.
Main Methods:
- Conducted an exome association study in 88 HCV-infected patients with and without liver fibrosis.
- Focused analysis on genes within the transforming growth factor-beta (TGF-β) signaling pathway.
- Performed replication studies in an additional cohort of 617 patients to validate findings.
Main Results:
- Identified an enrichment of rare variants in the endoglin gene (ENG) among patients with liver fibrosis.
- A specific ENG variant, Thr5Met, was significantly associated with fibrosis development.
- Carriers of the Thr5Met variant had an overall odds ratio of 3.04 for developing liver fibrosis.
Conclusions:
- Endoglin (ENG), a key component of TGF-β signaling, plays a role in HCV-related liver fibrogenesis.
- The identified ENG Thr5Met variant represents a potential genetic marker for fibrosis risk in HCV infection.
- Further research into endoglin's function could reveal novel therapeutic targets for liver fibrosis.
Abstract:
Despite the astonishing progress in treating chronic hepatitis C virus (HCV) infection with direct-acting antiviral agents, liver fibrosis remains a major health concern in HCV infected patients, in particular due to the treatment cost and insufficient HCV screening in many countries. Only a fraction of patients with chronic HCV infection develop liver fibrosis. While there is evidence that host genetic factors are involved in the development of liver fibrosis, the common variants identified so far, in particular by genome-wide association studies, were found to have limited effects. Here, we conducted an exome association study in 88 highly selected HCV-infected patients with and without fibrosis. A strategy focusing on TGF-β pathway genes revealed an enrichment in rare variants of the endoglin gene (ENG) in fibrosis patients. Replication studies in additional cohorts (617 patients) identified one specific ENG variant, Thr5Met, with an overall odds ratio for fibrosis development in carriers of 3.04 (1.39-6.69). Our results suggest that endoglin, a key player in TGF-β signaling, is involved in HCV-related liver fibrogenesis.
