Abstract 4139317: Epidemiologic and genetic associations between proteomic markers and thoracic aortic diameter

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.