Abstract Body (Do not enter title and authors here): Introduction
Enlargement of the thoracic aorta is clinically silent but predisposes to the highly morbid medical conditions of aortic dissection and rupture. Evidence suggests that clinical and genetic factors play a role in the pathogenesis of aneurysm. Here, we extend these efforts by identifying circulating proteomic markers linked to aortic diameter.

Research Question
We investigate whether circulating protein levels correlate with aortic diameter

Goals
1. Identify proteins whose circulating levels correlated with aortic diameter
2. Investigate whether protein levels may causally influence aortic diameter using Mendelian randomization

Methods
A total of 7,099 UK biobank participants had both ascending aortic diameter measured from MRI and 2,920 circulating proteomic markers measured with the Olink Explore 3072 panel. For each protein, a linear regression model was trained to estimate ascending aortic diameter, adjusted for age at time of MRI, time between Olink panel and MRI, and sex. A genome-wide association study (GWAS) of ascending aortic diameter was conducted after excluding participants related within 3 degrees of kinship to those with proteomic measurements, producing summary statistics for two-sample Mendelian randomization (2SMR). We used independent cis-protein quantitative trait loci (within 1 megabase of the gene) as the exposure and the ascending aortic diameter summary statistics as the outcome in a 2SMR framework.

Results
Circulating levels of 185 proteins were associated with ascending aortic diameter. Using 2SMR, we observed evidence consistent with a causal role for 43 proteins. Three proteins were significant in both analyses: CCN3 (a suppressor of vascular smooth muscle proliferation); BMP6 (a member of the TGF-beta superfamily); and RGMA (depleted in aortic plaques). Both analyses found a direct relationship between CCN3 levels and aortic diameter and an inverse relationship between BMP6 levels and aortic diameter. The 2SMR found a direct relationship between RGMA levels and aortic diameter, whereas the regression model found an inverse relationship.
The greatest 2SMR effect estimate was between greater levels of circulating methionine sulfoxide reductase A (involved in repair of oxidative damage in vascular smooth muscle cell mitochondria) and reduced ascending aortic diameter.

Conclusions
Circulating protein levels were associated with ascending aortic diameter, some of which may play causal roles in aneurysm development.