Host Gene Variants as Biomarkers for Stratification of Patients with Viral and Non-Viral Liver Diseases
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Perry, Kellie L
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Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) is increasing and has become a global health concern. Another important healthcare challenge is chronic infection with hepatitis C virus; this condition is often accompanied by hepatic steatosis. In both types of fatty liver disease, specific hepatic gene expression patterns contribute to individual predispositions to develop liver steatosis and its further progression to NASH. These expression patterns are influenced by specific gene variants carried in the genome of particular patients. The development of novel robust approaches to stratification of patients according to their individual predispositions is critical to maximize the effects of preventive and therapeutic interventions. Previous studies show that single-nucleotide polymorphism in IFNL3 gene (rs12979860) define probabilities of spontaneous and therapy-induced HCV clearance. Interestingly, IFN-λ4 protein can be generated only by individuals who carry ancestral, functional IFNL4-ΔG allele (rs368234815, or ss469415590). With a cohort of 40 patients, this study demonstrated an overall suppression of the transcription of genes associated with an inflammatory and interferon response in HCV infected patients who are carriers of beneficial, pseudogenic IFNL4-TT allele. This suppression was observed at the baseline, suggesting an intrinsic, pre-existing deregulation of the antiviral response in IFNL4 expression in carriers of IFNL4-ΔG allele. Additionally, we showed that the Day 7 course of treatment, patients with genotype IFNL4-TT undergo treatment-associated suppression of immune cells apoptosis, implying that more vigorous response to therapy may be mounted in this cohort. These findings provide additional insights into previously noted IFNL4-ΔG associated failure to achieve virological end-points in response to antiviral therapies. In the treatment-responsive carriers of beneficial IFNL4-TT allele, the most prominently suppressed pathway was “Glucocorticoid Receptor Signaling”. Additionally, Metacore-guided pathway analysis led us to hypothesize that patients with IFNL4-TT genotype may be less susceptible to the development of liver fibrosis due to the subsequent suppression of the expression of TGFβ receptor RIII. The latter prediction is independent of the presence or absence of HCV infection, and may be relevant to progression of both infectious and non-infectious liver diseases. A comparison of the disease-specific gene expression profiles from African American and Caucasian patients demonstrated that substantial differences between human races occur at the level of advanced chronic liver disease (NASH), but not at the level of simple steatosis which is known to be relatively benign in all ethnicities. In particular, we report intrinsic differences in the levels of compensatory anti-oxidative response as could be seen from the coordinated changes in the levels of Glutathione S-transferases 2, 4, and 5 in patients with NASH. We also compared gene expression patterns in NAFLD affected livers of African American and Caucasian patients and identified several potentially important hepatic genes over-expressed in African American patients. Many genes highlighted in our analysis contain polymorphic positions with allele frequencies substantially different between African American and Caucasian cohorts. Differences in distribution of genome variants in these populations may contribute to a degree of protection from the development of advanced non-infectious forms of chronic liver diseases observed in African American patients.
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This dissertation has been embargoed for 5 years and will not be available until November 2021 at the earliest.
Keywords
HCV, Biomarkers, Interferon, Viral, Variant