Genetic Polymorphisms of Type I Interferon Receptor 1 Affect the Susceptibility to Chronic Hbv Infection: Association Analysis and Mechanistic Investigation

This dissertation, "Genetic Polymorphisms of Type I Interferon Receptor 1 Affect the Susceptibility to Chronic HBV Infection: Association Analysis and Mechanistic Investigation" by 周婕, Jie, Zhou, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled: Genetic polymorphisms of type I interferon receptor 1 affect the susceptibility to chronic HBV infection: association analysis and mechanistic investigation Submitted by ZHOU JIE for the degree of Doctor of Philosophy at The University of Hong Kong in May 2007 Hepatitis B is a common and serious infectious disease of the liver, affecting more than 350 million people throughout the world. The Hepatitis B virus (HBV) infection leads to dichotomous clinical outcomes: viral clearance or viral persistence. Although the mechanisms underlying the distinct disease phenotypes have not been fully understood, host immunogenetics has been implicated in the susceptibility to chronic HBV infection. Type I interferons (IFN-α/β) function as the first line of host defense against viral infections based on their potent antiviral and immuno-modulatory effect. The exogenous administration or endogenous induction of IFN-α/β could inhibit the HBV replication in vitro and in vivo. Accumulating evidence suggests that the strength of host immune response in the early phase of HBV infection, which is closely related to IFN-α/β signaling, might be an important determinant for the clinical outcome of infection. The biological activities of IFN-α/β are mediated through type I interferon receptor, which consists of two subunits, IFNAR1 and IFNAR2. IFNAR1 is indispensable for the type I IFNs signaling. We thus hypothesize that the genetic variations in IFNAR1 may be associated with the susceptibility to chronic HBV infection. IFNAR1 gene polymorphisms were studied in a cohort of 756 Chinese and 114 Caucasian, and their effects on susceptibility to chronic HBV infection were analyzed. Selected variants were characterized phenotypically. The four DNA polymorphic sites identified in IFNAR1 promoter were -3, -77, -408, and -568, among which -3 and -408, as well as -77 and -568 were in complete linkage. The coding sequence of IFNAR1 was relatively conserved, with one SNP (19158C/G) resulting in a leucine to valine substitution in position 168 of the mature polypeptide. Polymorphism in 19158 was in strong linkage disequilibrium with that in -77 and -568 of IFNAR1 promoter. Genetic association analysis suggested the correlation of -77, -568, and 19158 polymorphisms to susceptibility to chronic HBV infection. However, promoter functional study showed that loci -77 and -568 might not encode functional polymorphisms. Therefore, their association with HBV infection might be attributed to the linkage disequilibrium with 19158C/G SNP or other causal factor(s). Further study is thus warranted to explore the functional implication of 19158C/G SNP. Association study also revealed that a -3 and -408 T tagging haplotype was associated with predisposition to chronic HBV infection. It was further validated that the -3T variant resulted in the decreased IFNAR1 expression due to its lower binding affinity to a transcription factor (PARP-1), which may play an essential role for IFNAR1 transcriptional regulation. Notably, it was demonstrated that PARP-1 could be suppressed by HBV replication both in vitro and in vivo. Taken together, we elucidate a mechanism by which the -3T variant increases susceptibility to chronic HBV infection. Upon HBV infection, the decr