Date of Award

12-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Nursing Science

Research Advisor

Ansley G. Stanfill, PhD

Committee

Ann Cashion, PhD; Tina Costacou, PhD; Margaret Harvey, PhD; Elizabeth A. Tolley, PhD ; David B. Wright, M.D.

Keywords

atherosclerosis;Coronary artery disease;genotyping;haptoglobin;prediabetes;risk

Abstract

Atherosclerotic cardiovascular disease (ASCVD) continues to be the leading cause of death worldwide. While several risk factors contributing to disease progression are well-known, pitfalls and limitations exist for estimating if or when an individual will develop the disease. Coronary artery disease (CAD), a subtype of ASCVD, causes myocardial infarction, contributing to significant morbidity and mortality. Current ASCVD risk estimator calculators lack comprehensiveness and do not include genetic or social determinants of health information, which are known to affect ASCVD risk.

Haptoglobin (Hp) genotype also influences CAD risk. Hp is a protein that binds free hemoglobin released from physiologic or pathologic erythrocyte turnover or destruction. If unbound, free hemoglobin causes oxidative stress, increasing the risk of atherosclerosis. The Hp genotype determines the haptoglobin protein’s effectiveness in entering tissues to bind the free hemoglobin. The three main Hp genotypes, Hp 1-1, Hp 2-1, and Hp 2-2, and their corresponding proteins, range from efficient to least efficient antioxidant, thereby influencing atherosclerosis risk. Hp 2-2 genotype has been shown to increase cardiovascular disease five times compared to the Hp 1-1 genotype in individuals with diabetes. Previous studies have dichotomized glycemia into diabetic and nondiabetic, not accounting for the spectrum of abnormal glucose and oxidative stress that exists with prediabetes and insulin resistance.

This dissertation aims to improve understanding of ASCVD risk estimation to describe how Hp genotyping affects CAD risk. First, a conceptual model that describes a more comprehensive ASCVD risk assessment approach than is currently used in clinical practice is described. This conceptual model depicts how adding social risk factors and Hp genotyping detects additional sources of increased oxidative stress, increasing ASCVD risk cumulatively. Next, a study was done that derived ASCVD risk scores from historical health records to determine the association between ASCVD risk score and CAD and carotid intima-media thickness (CIMT) in a sample of individuals with prediabetes. This study demonstrated that ASCVD risk score and category were not associated with a history of CAD but were associated and moderately correlated with CIMT measurements. Individuals with higher ASCVD risk scores were older and demonstrated higher systolic blood pressure and CIMT measurements. This study adds to existing literature that available ASCVD risk calculators may be suboptimal at estimating CAD risk, at least in some populations. Additionally, CIMT provides physiologic measurements to diagnose and track ASCVD, which is more clinically useful than ASCVD risk scores. Finally, a case-control study demonstrated Hp 2-2 genotype had four times higher odds of CAD compared to the Hp 1-1 genotype in individuals with prediabetes, supporting the compounded CAD risk of insulin resistance and abnormal glycemia with the Hp 2-2 genotype. Future research can build on these findings to include studies with larger numbers of participants and trials to see the effects of genotype-specific interventions on CAD risk and CIMT measurements.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

0000-0002-7830-8756

DOI

10.21007/etd.cghs.2023.0640

Additional Files
2023-028-Mewborn-DOA.pdf (274 kB)
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