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HOST GENETIC VARIANTS, TREATMENT OUTCOMES AND METABOLIC COMPLICATIONS IN HEPATITIS C VIRUS GENOTYPE-1

Iuliano, Angela Danielle (2008) HOST GENETIC VARIANTS, TREATMENT OUTCOMES AND METABOLIC COMPLICATIONS IN HEPATITIS C VIRUS GENOTYPE-1. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Chronic Hepatitis C Virus (HCV) infection is prevalent in approximately 3.2 million people in the United States. Understanding mechanisms of HCV treatment response and conditions seen in people with HCV such as steatosis and Insulin Resistance (IR) are important to preventing excess morbidity and mortality and improving HCV treatment outcomes. Host genetic factors may be important with respect to these issues. The purpose of this research was to investigate host genetic relationships with 28 day viral decline after treatment initiation, steatosis and insulin resistance and to examine these associations separately in African Americans and Caucasian Americans infected with HCV genotype-1. Data from the Study of Viral Resistance of Antiviral Therapy of Chronic Hepatitis C (Virahep-C) were used. Virahep-C was designed to understand the mechanisms of resistance to antiviral therapy for chronic HCV genotype-1 patients. The studies reported in this dissertation included up to 194 Caucasian Americans (CA) and 180 African Americans (AA) who agreed to participate in the Virahep-C genetics ancillary study. In longitudinal analyses of 28 day treatment induced viral decline, polymorphisms in Myxovirus resistance 2 (MX2), Oligoadenylate synthetase-like (OASL), Signal transducer and activator of transcription 1 and 2 (STAT1 and STAT2) were significantly associated with viral decline. Additionally, significant Protein Kinase (PKR) haplotype associations with viral decline were observed among AAs. In cross-sectional analyses, significant associations between selected genetic variants and either steatosis or IR were observed in Interleukin-10 (IL10), Leptin Receptor (LEPR), Interleukin-6 (IL6) and Transforming Growth Factor Beta 1 (TGF-â1) for both conditions. Statistically significant interactions were observed between IL10, LEPR and TGF-â1 polymorphisms and HOMA2-IR scores when examining steatosis.Statistically significant associations were observed for Adiponectin Receptor 1 (ADIPOR1) polymorphisms and 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (HMGCS2) polymorphisms and steatosis or IR. Overall, these findings suggest that host genetic factors are associated with treatment induced 28 day viral decline, steatosis and IR. Understanding the biological mechanisms that contribute to these findings has significant public health implications because it could help establish new therapies and interventions to prevent HCV related morbidity and mortality. Results may also contribute to understanding the mechanisms of treatment response, steatosis and IR.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Iuliano, Angela Danielleadi0623@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBelle, Stevenbelle@edc.pitt.eduSBELLE
Committee MemberWahed, AbdusWahedA@edc.pitt.eduWAHED
Committee MemberFeingold, Eleanorfeingold@pitt.eduFEINGOLD
Committee MemberZmuda, JosephZmudaJ@edc.pitt.eduEPIDJMZ
Committee MemberYee, LelandYeeL@edc.pitt.eduLJY5
Date: 25 June 2008
Date Type: Completion
Defense Date: 20 March 2008
Approval Date: 25 June 2008
Submission Date: 11 April 2008
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Epidemiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Genetic Variants; Genetics; HCV; Hepatitis C Virus; Insulin Resistance; Polymorphisms; Steatosis; Treatment Outcomes; Viral Decline
Other ID: http://etd.library.pitt.edu/ETD/available/etd-04112008-103521/, etd-04112008-103521
Date Deposited: 10 Nov 2011 19:35
Last Modified: 19 Dec 2016 14:35
URI: http://d-scholarship.pitt.edu/id/eprint/7006

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