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Hereditary pancreatitis: a prototype of chronic pancreatitis to characterize variable genomic elements that impact disease features and family dynamics

Shelton, Celeste (2019) Hereditary pancreatitis: a prototype of chronic pancreatitis to characterize variable genomic elements that impact disease features and family dynamics. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Pancreatitis is a complex acute and chronic inflammatory disease of the pancreas. Patients with chronic pancreatitis (CP) typically experience severe pain and loss of pancreatic function, and similar clinical phenotypes are produced by multiple genetic and environmental etiologies. However, the etiology of inflammation and the mechanisms behind risk for progression and outcomes remain obscure across different etiologies. Hereditary Pancreatitis (HP) is an autosomal dominant form characterized by disease onset in adolescence and progression to CP by adulthood. No effective treatment or therapeutic options exist, and the most advanced surgical option is total pancreatectomy with islet autotransplantation (TPIAT).
Existing patients and samples from the HP Study at the University of Pittsburgh were leveraged to evaluate disease outcomes and quality of life in the largest USA cohort. Phenotypic variability and co-existing risk variants for disease severity and pancreatic cancer were evaluated in HP pedigrees. Leftover TPIAT pancreatic tissue from patients with CP was used to investigate underlying gene expression profiles.
Risk of pancreatic cancer was significantly greater than age- and sex-matched SEER data (SIR 59), but the cumulative risk was 7.2% (95% CI 0-15.4) at 70 years, which is much lower than previous reports. Mental and physical quality of life was found to be significantly reduced in individuals with HP compared to family controls. Expression of worry and impact on family dynamics was identified from qualitative data. Phenotypic variability within and between HP pedigrees was identified for age of onset, penetrance and pancreatic cancer, for which one pancreatic cancer family harbored a predicted risk modifying ATM variant. RNA-sequencing studies indicated the upregulation of immune-signaling pathways and identified a new dedifferentiated cell population indicative of a regeneration response.
Accurately defining risk for pancreatitis and outcomes is critical to improving patient counseling and management, and for surgical decision making. Furthermore, RNA-Sequencing provides a new opportunity to understand molecular pathogenesis in CP tissue and identify possible therapeutic targets for future research. Improvements in risk classification, early diagnosis and counseling strategies, and the development of targeted treatment approaches has important public health implications for healthcare spending, pain management and health-related quality of life.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Shelton, Celestecas186@pitt.educas186
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorWhitcomb,
Committee MemberGrubs,
Committee MemberMinster,
Committee MemberYadav,
Date: 27 June 2019
Date Type: Publication
Defense Date: 5 February 2019
Approval Date: 27 June 2019
Submission Date: 5 March 2019
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 229
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: pancreatitis, hereditary pancreatitis, PRSS1, pancreatic cancer, RNA-Sequencing, heritability, quality of life, genetic counseling, family perspectives
Date Deposited: 27 Jun 2019 17:53
Last Modified: 28 Jun 2019 14:14


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