IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction

Area of Science:

• Immunogenetics
• Hepatology
• Viral Hepatitis Research

Background:

• Chronic hepatitis C virus (HCV) infection affects 3% of the global population, potentially leading to cirrhosis and liver cancer.
• Current antiviral treatments for HCV remain suboptimal, highlighting the need for improved patient management strategies.
• Genome-wide association studies (GWAS) previously identified the rs12979860 polymorphism near IL28B as a predictor of HCV clearance.

Purpose of the Study:

• To identify novel genetic predictors of HCV clearance.
• To investigate the functional role of identified polymorphisms in IL28B gene regulation.
• To evaluate the clinical utility of a novel TT/-G polymorphism compared to rs12979860 for predicting HCV clearance.

Main Methods:

• Genotyping of TT/-G and rs12979860 polymorphisms in individuals with varying HCV clearance outcomes.
• Analysis of peripheral blood mononuclear cells (PBMCs) to assess gene expression.
• Quantitative analysis of IL28B and IFN-γ-inducible protein 10 (IP-10) mRNA induction.

Main Results:

• A novel TT/-G polymorphism in the CpG region upstream of IL28B was identified as a superior predictor of HCV clearance compared to rs12979860.
• The TT/-G polymorphism, but not rs12979860, was shown to be essential for the induction of IL28B and IP-10 mRNA in PBMCs.
• TT/-G represents the first identified functional genetic variant influencing IL28B expression related to HCV clearance.

Conclusions:

• The TT/-G polymorphism is a more accurate predictor of HCV clearance than rs12979860.
• This novel variant provides critical insights into the genetic mechanisms regulating IL28B and HCV clearance.
• Implementing TT/G genotyping in clinical practice could significantly improve the management of patients with hepatitis C.