Abstract 19857: Genome Wide Association With Aortic Dimension in Bicuspid Aortic Valve Disease

Introduction: Ascending aortic dilation occurs frequently in patients with a bicuspid aortic valve (BAV) and is a source of morbidity and mortality, but its causes are incompletely known. Hypothesis: The objective of this study was to identify genetic markers and chromatin looping associated with aortic dimension in a cohort with BAV. Methods: 404 Caucasian patients with BAV were genotyped using Illumina Omni-2.5. Patients were predominantly ascertained at or after surgery for thoracic aortic aneurysm (44%) or aortic valve disease (46%). Aortic root and ascending aortic dimensions were measured or abstracted from medical records using standardized echocardiography and CT measurements. The largest aortic dimension recorded in either the aortic root or ascending aorta was used for analysis. Genomic data were imputed against 1000 Genome project (Phase 3) using Impute2. Quality control of data and association analysis was implemented by PLINK. Association tests were carried out using linear regression, adjusting for age and gender. Chromatin looping was examined using GWAS3D and ChIA-PET and Hi-C data. Results: 404 patients, 74% male, aged 54±11 years with average largest aortic dimension of 40±7 mm were examined. We identified four loci associated with aortic dimension at GWAS threshold; rs144880401 (6p21.2; P=9х10 -10 , 11mm), rs114680042 (1q25.3; P=6х10 -9 , 11mm), rs62556138 (9q22; P=8х10 -9 , 7mm) and rs78310353 (1q41; P=1.5х10 -8 , 11mm). Two additional loci near genes previously associated with cardiovascular or aortic disease were identified at lower levels of significance, r28611325 (17q25.3; P=1х10 -7 , 11mm) and rs4141713, rs10118880 (9p21.3; P=5х10 -5 ). We identified a chromatin interaction looping between tophit SNP (rs144880401) and 245kb upstream from promoter region of VEGFA (6p21.1; CP=9х10 -14 ), which has been previously associated with aortic aneurysm. We also identified a regulatory signal (rs74899022; P=6х10 -6 , 6mm) in ESRRG (1q41) which activates GATA4 . ESRRG also induces angiogenesis by direct transcriptional activation of VEGFA . Conclusions: We observed genes associated with aortic dimension, perhaps mediated through epigenetic mechanisms. Findings in VEGFA and ESRRG require further mechanistic studies.