Using the All of Us Research Program to identify novel risk factors for aortic aneurysms
Embargo Date
2028-02-11
OA Version
Citation
Abstract
OBJECTIVE: Aortic aneurysms (AA) are some of the most serious and life-threatening cardiovascular diseases (CVD). Once a rupture or dissection of the aortic wall occurs, 50% of patients die before getting medical attention. Well-established risk factors include smoking, chronic high blood pressure, high cholesterol, and atherosclerosis. These are some of the most common chronic issues among the US population. While lifestyle and behavioral factors contribute to the risk of AA and other CVD, some genetic mutations also predispose people to higher risk of AA. Those who have Marfan syndrome, Ehlers-Danlos syndrome, and other connective tissue-related diseases are at higher risk for developing AA, mainly in the thoracic portion of the aorta. Understanding which genetic mutations, or SNPs, are associated with increased risk of AA can play a critical role in precision medicine to help those who are genetically predisposed manage this disease better and lower the risk of death through targeted therapies and potential early screenings and monitoring. The goal of this project was to use a recently established and publicly available human dataset from the All of Us Research Program to identify novel risk factors for abdominal and thoracic aneurysms. Specifically, we hypothesized that circulating glucose and cholesterol contribute to the development of AA, independently of being diabetic or having atherosclerosis.
METHODS: To test our hypothesis, I first extracted data from the All of Us (NIH) dataset; I then used logistic regressions to determine associations between low, medium, and high levels of glucose (Hemoglobin A1C) or cholesterol (total, HDL, LDL and LDL/HDL ratio) and AA. The analyses were run separately for thoracic aortic aneurysms (TAA) and abdominal aortic aneurysms (AAA) as these forms of AA are generally considered to have different pathogenesis with TAA being genetically affected, whereas AAA is linked mainly to lifestyle factors.
RESULTS: Prediabetic A1C levels were associated with increased odds of having AAA (OR=1.15, 95% CI [1.01,1.30], p=0.0333) after adjusting for race, ethnicity, gender/sex, and age. On the contrary, after adjusting for the same demographic variables, higher A1C levels were associated with decreased odds of having TAA for both Prediabetics (OR=0.85, 95% CI [0.76, 0.95], p=0.0058) and Diabetics (OR=0.56, 95% CI [0.48, 0.66], p<0.0001). Similarly, slightly elevated (At-Risk) total cholesterol levels were associated with decreased odds of having AAA (OR=0.65, 95% CI [0.44, 0.96], p=0.0303) after adjusting for race, ethnicity, gender/sex, and age. Using the same controlled variables, both At-Risk (OR=0.77, 95% CI [0.765, 0.774], p<0.0001) and High (OR=0.73, 95% CI [0.725, 0.740], p<0.0001) total cholesterol levels were associated with decreased odds of having TAA. After controlling for race, ethnicity, gender/sex, and age, lower levels of HDL, a form of cholesterol considered protective for CVD, were associated with increased odds of having AAA (At-Risk: OR=1.27, 95% CI [1.02, 1.60], p=0.0363; Low: OR=1.50, 95% CI [1.23, 1.84], p<0.0001). Moreover, increased levels of LDL, also known as “bad” cholesterol, were associated with decreased odds of having TAA, after controlling for race, gender/sex, ethnicity, and age (At-Risk: OR=0.79, 95% CI [0.787, 0.798], p<0.0001; High: OR=0.57, 95% CI [0.56, 0.58], p<0.0001). A higher LDL/HDL ratio was associated with decreased odds of having TAA (OR=0.852, 95% CI [0.851, 0.853], p<0.0001).
CONCLUSION: The results suggest that circulating glucose may have a protective effect against TAA but a detrimental effect for AAA. Higher HDL cholesterol levels may also provide a protective effect against AAA, while increased total and LDL cholesterol seem to have a protective affect against TAA, along with a larger LDL/HDL ratio. Future analyses, however, should control for medication usage, specifically for anti-diabetic and cholesterol-lowering medications, in order to fully understand the association between circulating glucose or cholesterol and AA.
Description
2025