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dc.contributor.authorHanson, Jacquelynen_US
dc.date.accessioned2017-03-13T20:17:57Z
dc.date.issued2017
dc.identifier.urihttps://hdl.handle.net/2144/20799
dc.description.abstractWild-type transthyretin amyloidosis (ATTRwt) is a rare, sporadic protein misfolding disorder with no validated biomarkers or specific treatments. The disease is characterized by deposition of amyloid fibrils composed of wild-type transthyretin (TTR) in cardiac tissue, which leads to cardiomyopathy, heart failure, and death within 5 years. The hypothesis for the studies detailed in this dissertation was non-coding variants in the TTR gene regulatory regions impact expression and serum levels of the protein, thereby contributing to ATTRwt pathogenesis. Investigations included examination of 2 enhancer regions and the proximal promoter of the TTR gene for risk factors which could contribute to pathogenesis of ATTRwt amyloidosis. In total, 11 common and 20 rare variants were identified. The analyses demonstrated significant associations of 3 variants with increased disease risk and 4 variants with age at disease onset and/or survival. Functional studies using GFP and luciferase reporter assays in HepG2 cells were performed to examine the impact of nucleotide alterations in the TTR proximal promoter on reporter expression. Three ATTRwt-risk factors (rs3764479, rs72922940, rs3794885), caused significantly decreased reporter expression in both GFP and luciferase assays (p < 0.02). Moreover, serum TTR levels, measured by immunoturbidity and analyzed along with ATTRwt clinical data, demonstrated that lower serum TTR concentrations were associated with worse survival (hazard ratio = 0.89, p = 0.003). Follow-up analysis of an ATTRwt subset treated with diflunisal, a TTR stabilizer, showed increased serum TTR (p = 0.002) and organ improvement as assessed by cardiac biomarkers (p = 0.043). Unexpectedly, our genetic sequencing data suggested that the TTR G6S variant was disease-protective. Analysis of the TTR G6S protein using circular dichroism and aggregation assay corroborated these findings by demonstrating a higher structural stability and a lower aggregation propensity compared to L55P and V122I, two unstable amyloidogenic TTR variants. In summary, the major findings of this work were: 1) identification of genetic variants that confer risk for ATTRwt amyloidosis through changes in expression, 2) evidence in support of serum TTR as a candidate for monitoring disease progression and response to treatment, and 3) evidence suggesting that TTR G6S may confer protection from ATTRwt by slowing the amyloid cascade.en_US
dc.language.isoen_US
dc.rightsAttribution-NonCommercial 4.0 Internationalen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectAgingen_US
dc.subjectAmyloidosisen_US
dc.subjectRisk factorsen_US
dc.subjectTransthyretinen_US
dc.titleTransthyretin gene regulation in wild-type transthyretin amyloidosisen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2017-03-09T02:07:19Z
dc.description.embargo2017-09-08T00:00:00Z
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplinePathologyen_US
etd.degree.grantorBoston Universityen_US


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Except where otherwise noted, this item's license is described as Attribution-NonCommercial 4.0 International