Date of Award

5-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Healthcare Genetics

Committee Chair/Advisor

Tracy Fasolino

Committee Member

Stephanie Davis

Committee Member

Vivian Haley-Zitlin

Committee Member

Puya Yazdi

Committee Member

Joseph Bible

Abstract

This dissertation investigates the relationship between the omega-6 fatty acid, linoleic acid (LA), and the cardiovascular disease (CVD) risk marker apolipoprotein B (apoB). ApoB is considered to be the most important causal marker of CVD. However, the impact of LA on CVD risk has been subject to debate within the scientific literature, with various studies showing LA can decrease or increase apoB concentrations. To foster more clarity regarding this relationship, we first investigated all dietary, macronutrient, micronutrient, and nutrigenetic factors that impact concentrations of apolipoproteins via a narrative analysis approach. We found that more Westernized diets containing more processed foods, sugars, and saturated fats were more likely to raise apoB. In contrast, Mediterranean diets rich in vitamins, minerals, fiber, and omega-3 were more likely to decrease apoB. We then conducted a systematic review of randomized controlled trials investigating LA's impact on apoB, specifically noting for cooking with LA-containing seed or vegetable oil. While 133 studies were initially screened, only 3 met the inclusion criteria. None of the studies specifically evaluated cooking with LA-containing oil as an intervention, and only the three mentioned cooking with LA-containing oil as an option for exposure. No consensus was found among the three included studies regarding the impact on apoB. Since the most common exposure to LA-containing oil is via heated cooking, we suggest future studies evaluate this topic. We then explored a causal association of LA on apoB via a Mendelian Randomization approach. In this study, omega-6 polyunsaturated fat levels serve as the instrumental variable, LA is the exposure variable, and apoB is the outcome variable. Data for this study was obtained from the UK Biobank. To avoid confounders of the relationship between LA and apoB, subjects with a previous diagnosis of heart disease or on cholesterol-lowering medications, such as statins, were not included. A statistically significant correlation was found between LA and apoB when accounting for confounders of this relationship, with a two-stage least-squares analysis finding a causal association of LA on apoB concentrations, with the first stage of the analysis yielding an eigenvalue of 755.785 and F-statistic of 2796.93 and the second stage of the analysis yielding a statistically significant Wald chi2 value of 27276.48 and R2 of 0.6185. The findings from this study suggest a causal association of LA on apoB levels. When coupled with the conclusions of the previously mentioned studies, future investigations should seek to clarify the relationship between LA and apoB while accounting for the consumption of oxidized LA metabolites as well as genetic impacts on the metabolism of LA and its oxidized metabolites.

Author ORCID Identifier

0000-0002-4156-7332

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