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You searched for +publisher:"Vanderbilt University" +contributor:("Nancy J. Brown"). Showing records 1 – 3 of 3 total matches.

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Vanderbilt University

1. Shuey, Megan Marie. Pharmacogenetics of Resistant Hypertension: Leveraging the Electronic Medical Record.

Degree: PhD, Pharmacology, 2018, Vanderbilt University

Patients with resistant hypertension have uncontrolled blood pressure despite concurrent treatment with three or more antihypertensive medications including a thiazide diuretic. Compared to patients with controlled hypertension, resistant hypertensive patients are at an increased risk for myocardial infarction, stroke, and renal disease. Despite these risks, the pathophysiology underlying resistant hypertension remains poorly understood and very few novel antihypertensive medications have been discovered to treat the condition. We hypothesized that we could use electronic medical records (EMRs) to identify patients with resistant hypertension for use in epidemiologic and genetic studies. Using the Vanderbilt University Medical Center (VUMC) EMRs we identified patients with resistant hypertension. Consistent with previous clinical studies, the prevalence of resistant hypertension in the EMR-derived populations was greater among African Americans compared to European Americans, and patients with resistant hypertension were significantly older, heavier, more likely to have chronic kidney disease stage three, and had a higher incidence of type 2 diabetes mellitus than patients with controlled hypertension. We also identified significant differences in the pharmacologic treatment of resistant hypertension in African Americans and European Americans in an academic medical center . To demonstrate the potential for EMR-derived resistant hypertension populations to be used in genetic studies, we used the Department of Veteran Affairs Million Veterans Program database to test for an association between two loss-of-function variants in CYP4A11 and resistant hypertension. We determined there was a significant association between the two CYP4A11 variants, rs1126742 and rs3890011, and resistant hypertension (β=0.04, p=0.02; β=0.05, p<0.001, respectively). Finally, using the VUMC EMR-derived resistant hypertension population we developed an algorithm to determine the blood pressure response to spironolactone. We determined that approximately 29% of patients with resistant hypertension do not respond to spironolactone. Higher blood pressure and changes in serum sodium, potassium and creatinine were associated with the blood pressure response to spironolactone, consistent with spironolactone’s mechanism of action to block the mineralocorticoid receptor and decrease activity of the epithelial sodium channel. Advisors/Committee Members: James M. Luther (committee member), Alan Brash (committee member), Joshua C. Denny (committee member), Nancy J. Brown (committee member), Dan Roden (Committee Chair).

Subjects/Keywords: CYP4A11; Blood Pressure response; Resistant Hypertension; Antihypertensive Medications; Electronic Medical Records; Spironolactone

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Shuey, M. M. (2018). Pharmacogenetics of Resistant Hypertension: Leveraging the Electronic Medical Record. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/15419

Chicago Manual of Style (16th Edition):

Shuey, Megan Marie. “Pharmacogenetics of Resistant Hypertension: Leveraging the Electronic Medical Record.” 2018. Doctoral Dissertation, Vanderbilt University. Accessed April 13, 2021. http://hdl.handle.net/1803/15419.

MLA Handbook (7th Edition):

Shuey, Megan Marie. “Pharmacogenetics of Resistant Hypertension: Leveraging the Electronic Medical Record.” 2018. Web. 13 Apr 2021.

Vancouver:

Shuey MM. Pharmacogenetics of Resistant Hypertension: Leveraging the Electronic Medical Record. [Internet] [Doctoral dissertation]. Vanderbilt University; 2018. [cited 2021 Apr 13]. Available from: http://hdl.handle.net/1803/15419.

Council of Science Editors:

Shuey MM. Pharmacogenetics of Resistant Hypertension: Leveraging the Electronic Medical Record. [Doctoral Dissertation]. Vanderbilt University; 2018. Available from: http://hdl.handle.net/1803/15419


Vanderbilt University

2. Kodaman, Nuri. The Genetics of Cardiovascular Risk Factor Correlations.

Degree: PhD, Human Genetics, 2015, Vanderbilt University

Cardiovascular disease (CVD) is the leading cause of death worldwide. The vast possibilities of interaction between genetic and environmental factors that contribute to CVD can be simplified by identifying conditions that favor the emergence of specific risk factor networks. If the relationships among CVD risk factors that give rise to these networks are under genetic control, then such relationships can be considered heritable phenotypes in themselves, amenable to genetic analysis. We characterized correlational networks of cardiovascular risk factors in a large cohort of urban and rural men and women in Ghana, and investigated how they may be perturbed by factors such as sex and urban lifestyle. We also assessed the comparative relevance of individual risk factors to thrombosis within and across networks, using as a proxy their association with an intermediate phenotype of CVD, plasminogen activator inhibitor type-1 (PAI-1). We found that the relationships between risk factors and PAI-1 were far more sensitive to differences in sex and environment than were the relationships among the risk factors themselves. To lay the theoretical groundwork for our subsequent genetic analyses, we modeled multiple types of biological SNP-by-covariate interactions and derived the statistical parameters to which they should give rise. In doing so, we demonstrated that even the strongest gene-by-covariate interactions at the biological level could display weak statistical interactions using general linear models. Moreover, we quantified the expected strength of the interaction relative to the marginal effect, depending on the nature of biological interaction. We then developed the ordinal joint interaction model (OJIM), which can not only identify biological SNP-by-covariate interactions where they exist, but also pick up marginal effects and leverage the change in residual correlation induced by marginal effects. In our analyses of the Ghanaian study population, the OJIM had more power than univariate or bivariate analysis to detect lipid SNPs of known biological significance, indicating that context-dependent genetic effects are probably quite common, and that the OJIM can identify them where they exist. We also used the OJIM to interrogate exome-wide data of our Ghanaian study population, and identified genetic variants that may increase thrombotic risk by influencing the covariance between these risk factors and PAI-1. Advisors/Committee Members: Nancy J. Brown (committee member), David E. McCauley (committee member), Melinda C. Aldrich (committee member), Douglas P. Mortlock (Committee Chair).

Subjects/Keywords: genetic epidemiology; epidemiology; GXE interaction; t-PA; West Africa; fibrinolysis; cardiovascular disease risk factors; method development; ordinal regression

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Kodaman, N. (2015). The Genetics of Cardiovascular Risk Factor Correlations. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/15219

Chicago Manual of Style (16th Edition):

Kodaman, Nuri. “The Genetics of Cardiovascular Risk Factor Correlations.” 2015. Doctoral Dissertation, Vanderbilt University. Accessed April 13, 2021. http://hdl.handle.net/1803/15219.

MLA Handbook (7th Edition):

Kodaman, Nuri. “The Genetics of Cardiovascular Risk Factor Correlations.” 2015. Web. 13 Apr 2021.

Vancouver:

Kodaman N. The Genetics of Cardiovascular Risk Factor Correlations. [Internet] [Doctoral dissertation]. Vanderbilt University; 2015. [cited 2021 Apr 13]. Available from: http://hdl.handle.net/1803/15219.

Council of Science Editors:

Kodaman N. The Genetics of Cardiovascular Risk Factor Correlations. [Doctoral Dissertation]. Vanderbilt University; 2015. Available from: http://hdl.handle.net/1803/15219


Vanderbilt University

3. White, Marquitta Jonisse. Genetics of Plasminogen Activator Inhibitor – 1: a potent biological effector of cardiovascular disease risk.

Degree: PhD, Human Genetics, 2014, Vanderbilt University

Cardiovascular disease (CVD) is an inclusive term encompassing several disorders of the circulatory system that together account for the majority of global non-communicable disease (NCD) mortality. Major thrombotic events, due in part to impaired fibrinolysis, are a unifying characteristic of several CVDs. Plasminogen activator inhibitor-1 (PAI-1) is a major regulator of fibrinolysis, and PAI-1 levels associate with CVD susceptibility and severity in several populations. The main objectives of this dissertation were to evaluate the genetic impact of common single nucleotide polymorphisms (SNPs) on inter-individual variation in PAI-1 levels in a Ghanaian population, and present a novel method to identify candidate genes for prioritization in future studies. We discovered novel associations between single variants in the arylsulfatase b (ARSB), carboxypeptidase A2 (CPA2), and leukocyte receptor cluster member 9 (LENG9) and median PAI-1 levels. Quantile regression analyses directed at the upper quartile of the PAI-1 distribution was performed to uncover novel variants with significant impact on this clinically relevant portion of the PAI-1 distribution. Upper quartile regression analyses revealed significant associations between single variants in period circadian clock 3 (PER3), a discovery that supports previous evidence of the involvement of the circadian pathway in regulation of PAI-1 levels in Caucasian populations as well as model organisms. This finding suggests that the significance of the circadian pathway as a whole may be generalizable across populations, even though gene effects may be population specific. We present a novel approach; Multi-lOcus based selection of Candidate genes (MOCA), which incorporates multi-variant association signals into the prioritization of genes for further evaluation. MOCA identified four significantly associated loci; these loci included 28 novel candidate genes for PAI-1 levels. Each MOCA identified locus was located within previously identified CVD and/or PAI-1 related quantitative trait loci (QTL). Advisors/Committee Members: Nancy J. Brown (committee member), melinda aldrich (committee member), Dana Crawford (committee member), Jason Moore (committee member), Scott M. Williams (committee member), Bingshan Li (Committee Chair).

Subjects/Keywords: population genetics; plasminogen activator inhibitor-1; cardiovascular disease

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

White, M. J. (2014). Genetics of Plasminogen Activator Inhibitor – 1: a potent biological effector of cardiovascular disease risk. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14029

Chicago Manual of Style (16th Edition):

White, Marquitta Jonisse. “Genetics of Plasminogen Activator Inhibitor – 1: a potent biological effector of cardiovascular disease risk.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed April 13, 2021. http://hdl.handle.net/1803/14029.

MLA Handbook (7th Edition):

White, Marquitta Jonisse. “Genetics of Plasminogen Activator Inhibitor – 1: a potent biological effector of cardiovascular disease risk.” 2014. Web. 13 Apr 2021.

Vancouver:

White MJ. Genetics of Plasminogen Activator Inhibitor – 1: a potent biological effector of cardiovascular disease risk. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Apr 13]. Available from: http://hdl.handle.net/1803/14029.

Council of Science Editors:

White MJ. Genetics of Plasminogen Activator Inhibitor – 1: a potent biological effector of cardiovascular disease risk. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/14029

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