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The TGFB1 -509C/T polymorphism and elevated TGF-β1 levels are associated with chronic hepatitis C and cirrhosis
William Botelho de Brito1, Maria Alice Freitas Queiroz2, Ednelza da Silva Graça Amoras2
1Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará (Universidade Federal do Pará - UFPA), Belém, Pará, Brazil; Graduate Program in Virology, Evandro Chagas Institute/SVS/MS, Brazil.
Insights
The TGFB1 gene polymorphism increases hepatitis C virus (HCV) infection risk and disease progression. This genetic variation leads to higher TGF-β1 levels, which suppress IFN-γ, worsening liver damage and cirrhosis.
Area of Science:
- Immunology
- Genetics
- Hepatology
Background:
- Interferon-gamma (IFN-γ) and Transforming Growth Factor-beta 1 (TGF-β1) cytokines have opposing roles in immune responses.
- Genetic variations (polymorphisms) in IFNG and TGFB1 genes may alter cytokine levels and impact chronic Hepatitis C Virus (HCV) infection outcomes.
Purpose of the Study:
- To investigate the association between IFNG +874A/T and TGFB1 -509 C/T gene polymorphisms and chronic HCV infection.
- To examine the relationship between these polymorphisms, plasma cytokine levels, and HCV disease severity.
Main Methods:
- Real-time PCR was used to identify IFNG +874A/T and TGFB1 -509 C/T polymorphisms in 99 chronic HCV patients and 300 healthy controls.
- Enzyme-linked immunosorbent assay (ELISA) measured plasma levels of IFN-γ and TGF-β1.
- Statistical analysis correlated genotypes, cytokine levels, and disease stage.
Main Results:
- The TGFB1 -509 C/T polymorphism (TT genotype) was linked to increased HCV infection risk (OR=2.0465, p=0.0091).
- Higher plasma IFN-γ levels were observed in TT genotype carriers and patients with fibrosis or high inflammation.
- Elevated TGF-β1 levels were found in HCV patients, TT genotype carriers, and those with cirrhosis. A negative correlation existed between IFN-γ and TGF-β1 levels (p=0.0001).
Conclusions:
- The TGFB1 -509 C > T polymorphism is a risk factor for chronic hepatitis C.
- This polymorphism increases TGF-β1, which may inhibit IFN-γ, promoting disease progression towards cirrhosis.
Abstract:
The IFN-γ and TGF-β1 cytokines perform antagonistic activities in the immune response, and polymorphisms in these genes may induce changes in their plasma levels and influence the course of chronic Hepacivirus C (HCV) infection. The present study evaluated the IFNG +874A/T and TGFB1 -509 C/T polymorphisms in 99 samples from patients with chronic hepatitis C and in 300 samples from healthy donors, and the present study also investigated the association of cytokine plasma level with disease stage. Polymorphisms were identified by real-time PCR, and cytokine levels were measured by enzyme-linked immunosorbent assay. The frequency of the IFNG +874A/T polymorphic allele was not associated with susceptibility to HCV infection, but it was associated with lower inflammatory activity (p = 0.0432). The frequency of the TGFB1 -509C/T polymorphic (TT) genotype was associated with HCV infection (p = 0.0062) and a higher risk of infection (OR = 2.0465; p = 0.0091). Plasma levels of IFN-γ were higher in TT genotype carriers among the control (p = 0.0012) and HCV groups (p = 0.0064) as well as in patients with fibrosis (p = 0.0346) and patients with a high degree of inflammatory activity (p = 0.0381). The highest TGF-β1 levels were found in HCV-infected (p = 0.0329) individuals and in TT genotype carriers. Patients with cirrhosis had higher TGF-β1 (p = 0.0400). IFN-γ and TGF-β1 levels showed a negative correlation (p = 0.0001). In conclusion, the TGFB1 -509C > T polymorphism is associated with a risk of developing chronic hepatitis C, leading to increased TGF-β1, which inhibits IFN-γ production, contributing to the progression to cirrhosis.
