1)The Role of Sucrose Non-Fermenting Related Kinase in Ameliorating Aortic Endothelial Dysfunction &amp; Atherosclerotic Risk 2)Can Literature Weighted GRS for Height Predict Beta Cell Function and Insulin Resistance in Han Chinese?

Teng, Chih Yun Angelica

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Year:: 2017
Contributor:: Teng, Chih Yun Angelica (creator); Liu, Simin (Advisor); Xu, Haiyan (Reader); Chan, Juliana (Reader); Brown University. School of Public Health (sponsor)
Genre:: theses
Subject:: Inflammation; Atherosclerosis; Genome Wide Association; Genetic Risk Score; Height; Pancreatic beta cells; SNRK; Han Chinese; Hong Kong; Primary Aortic Endothelial Cell
Extent:: v, 151 p.
DOI: https://doi.org/10.7301/Z03R0RB5

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Abstract:: The Role of Sucrose Non-Fermenting Related Kinase in Ameliorating Aortic Endothelial Dysfunction & Atherosclerotic Risk Background - Atherosclerotic complications such as ischemic heart disease and stroke are leading contributors to worldwide mortality. Hyperlipidemia and insulin resistance trigger inflammatory pathways that promote endothelial dysfunction and arterial remodeling. As independent studies have identified sucrose nonfermenting kinase (SNRK) as both a potential inflammatory suppressant and fatty acid oxidation regulator, this molecule may be an understudied mediator of atherosclerotic risk. Aims - This study seeks to test the hypothesis that SNRK attenuates inflammation and is necessary for maintaining healthy endothelial cell surface integrity resistant to leukocyte rolling, infiltration, and subsequent plaque formation. Methods - We quantified SNRK gene expression alongside primary human aortic endothelial cell surface markers following incubation with varying concentrations of TNF α, fatty acid mixture, insulin, and insulin sensitizer- Rosiglitazone. Loss of function/knockdown studies using short-hairpin interfering RNA introduced via adenoviral transfection were attempted to determine the role that SNRK plays in regulating endothelial cell function. Results - TNFα significantly reduced SNRK expression levels by 65% (0.3472 ± 0.06, p<0.01). FFA concentrations of 0.2mM (0.97±0.14) and 0.5mM (0.75 ± 0.19) suppressed SNRK gene expression in a dose-dependent pattern, though results did not achieve statistical significance (p>0.1). No significant SNRK knock-down was achieved via adenovirus carriers due to low infection efficiency (40-50%). Up-regulation of SNRK expression was observed following a 24-hour incubation with 100nM insulin (1.47± 0.22) and 12-hour incubation with 10μM Rosiglitazone (1.11±0.45). Can Literature Weighted GRS for Height Predict Beta Cell Function and Insulin Resistance in Han Chinese? A GWAS & GRS Study using the Li Ka Shing & Hong Kong Diabetes Registry Background - Several gene loci associated with height have been inversely associated with Type 2 Diabetes and Gestational Diabetes, but the majority of reported loci have been sourced from European populations. Objective/Methods - To fill the gap in literature for populations of East Asian descent, we conducted a genome wide association study (GWAS) using genotyped data from 5957 diabetic subjects from Hong Kong Diabetes Registry (HKDR) and 317 healthy controls from the Li Ka Shing (LKS) occupational study. Candidate SNPS were weighed using effect sizes (β) from pre-existing studies to generate a weighted gene risk score (GRS) for height. Using linear regression models, we analyzed whether height GRS could predict beta-cell function and insulin resistance among gestational diabetic mothers (n=1075) and their offspring (n=908) in a separate Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. Results– GWAS identified 19 literature validated SNPs in the HKDR/LKS cohort that were significantly (1x10-4) associated with height and replicated in pre-existing literature. However, the 19 SNP literature weighted score was not associated with home assessment model measures of β-cell function nor insulin resistance among our non-diabetic controls (LKS) or HOPA mothers and offspring cohorts.
Notes:: Thesis (M. P. H.)--Brown University, 2017

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Teng, Chih Yun Angelica, "1)The Role of Sucrose Non-Fermenting Related Kinase in Ameliorating Aortic Endothelial Dysfunction & Atherosclerotic Risk 2)Can Literature Weighted GRS for Height Predict Beta Cell Function and Insulin Resistance in Han Chinese?" (2017). Public Health Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.7301/Z03R0RB5

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Public Health Theses and Dissertations

Theses and Dissertations for the Public Health department.
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1)The Role of Sucrose Non-Fermenting Related Kinase in Ameliorating Aortic Endothelial Dysfunction & Atherosclerotic Risk 2)Can Literature Weighted GRS for Height Predict Beta Cell Function and Insulin Resistance in Han Chinese?