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Identification of Metabolic, Immune, and Genetic Risk Factors for Hepatocellular Carcinoma

Thomas, Claire Elizabeth (2022) Identification of Metabolic, Immune, and Genetic Risk Factors for Hepatocellular Carcinoma. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Hepatocellular carcinoma (HCC) is a multifactorial common malignancy with poor prognosis. Rising incidence of HCC may be due to increasing prevalence of obesity, type II diabetes, and non-alcoholic fatty liver disease (NAFLD). The majority of HCC cases develop in the presence of chronic liver disease, whether that damage is caused by chronic hepatitis, alcohol abuse and/or NAFLD. Novel non-invasive biomarkers for altered metabolic and immune regulation of the liver may not only improve our understanding of hepatocarcinogenesis, but also aid in identification of individuals at high risk of developing HCC. Bile acid dysmetabolism, immune dysfunction cytokine markers, and underlying genetic predisposition to NAFLD may play a role in the development of HCC. However, prospective studies examining the association between these biomarkers and HCC risk, especially in Asian populations, are sparse.
This dissertation utilizes the resources of the Singapore Chinese Health Study (SCHS) and the Shanghai Cohort Study (SCS), two population-based prospective cohort studies. The first dissertation paper examines the association between pre-diagnostic serum bile acids and HCC risk in 100 case-control pairs in the SCHS. Higher levels of primary bile acids, specifically conjugated bile acids, were associated with higher risk of HCC. The second paper investigates the relationship between five CD8+ T cell-related cytokines and HCC risk in 315 case-control pairs in the SCS and 197 pairs in the SCHS. Higher levels of soluble CD137, a cytokine associated with inflammation and immune suppression, were associated with elevated risk of HCC in both cohorts independent of major risk factors for HCC. The third paper evaluates the association between a NAFLD-related polygenic risk score (PRS) and HCC risk in the SCHS using a mendelian randomization approach demonstrating that NAFLD may be causally associated with HCC risk in East Asians.
Taken together, the data show that bile acid dysmetabolism, the immune dysfunction cytokine soluble CD137, and genetic variants related to NAFLD contribute to the elevated risk of HCC, especially for individuals without traditional risk factors such as alcohol abuse and chronic hepatitis.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Thomas, Claire Elizabethcet53@pitt.educet530000-0001-9515-3277
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairYuan,
Committee MemberAdibi, Jennifer JADIBIJ@pitt.eduadibij
Committee MemberDiergaarde, Brendabbd3@pitt.edubbd3
Committee MemberKuipers, Allison Lkuipersa@edc.pitt.edukuipersa
Date: 10 May 2022
Date Type: Publication
Defense Date: 1 April 2022
Approval Date: 10 May 2022
Submission Date: 20 April 2022
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 160
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Epidemiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: epidemiology, hepatocellular carcinoma, cytokine, bile acids, non-alcoholic fatty liver disease, genetic risk score
Date Deposited: 10 May 2022 18:06
Last Modified: 10 May 2024 05:15


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