Influence of host genetics on the natural history of chronic liver diseases

Abstract

The value of polymorphisms near the interferon lamda 3 (IFNL3; formerly known as IL28B) for predicting response to PegIFNα/RBV treatment in HCV-1 is well established. In contrast, similar data for HCV-2/3 infection and its effect on inflammation and fibrosis, especially in non-HCV diseases remains contentious. The studies in this thesis were designed to clarify these issues. a) In an adequately powered study (n=1002 Caucasians patients), in patients with HCV-2/3 infection we demonstrated that IFNL3 genotype is the strongest baseline predictor of SVR. b) In a cohort of 4,172 patients, including 3,129 with chronic hepatitis C, 555 with chronic hepatitis B and 488 with non-alcoholic fatty liver disease, IFNL genotype is a strong aetiology-independent predictor of liver inflammation and fibrosis. c) We constructed an easy-to-use data mining based fibrosis prediction model incorporating IFNL genotype with other simple routinely available clinical and laboratory data. Our analysis of 4277 patients with liver diseases of different etiologies demonstrated that the risk of fast fibrosis progression, significant fibrosis and cirrhosis can be reliably estimated using the new model. The studies contained in this thesis augment our understanding of the effects of IFNL-genotype in the context of the natural history of chronic liver diseases.