The Heart Valve Society

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Novel Protective Genes Associated with Aortic Dilation in Bicuspid Aortic Valve Disease
Mahyar Heydarpour1, Martin Sigurdsson1, Karam Habchi1, Vanessa Montiero Vieira1, Tsuyoshi Kaneko1, Prem Shekar1, Thoralf Sundt, III2, Jochen Muehlschlegel1, B AV Consortium1, Simon C. Body1.
1Brigham and Women's Hospital, Boston, MA, USA, 2Massachusetts General Hospital, Boston, MA, USA.

OBJECTIVE:
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 unknown. Association of risk genes for thoracic aortic aneurysms and dissection (TAAD) syndromic-TAAD and non-syndromic-TAAD have been reported in previous studies, however genes protective for aortic dilation have not been examined. The aim of this study was to identify risk and protective genetic loci associated with aortic dimension in a cohort with BAV.
METHODS:
404 Caucasian (74% male) patients with BAV, presenting for surgery for thoracic aortic aneurysm (44%) or aortic valve disease (46%) were genotyped using Illumina Omni-2.5 and imputed against the 1000 Genomes Caucasian dataset using Impute2. 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 (mean 407 mm) was used for analysis. Quality control of data and association analysis was implemented using PLINK. Association tests were carried out using linear regression, adjusting for age and gender. Permutation testing was implemented to adjust p-values in haplotype analyses.
RESULTS:
We identified four risk, and three protective, loci associated with largest aortic dimension. This association was present when aortic dimension was normalized to Z-score (Campens et al.). We also identified two haplotype blocks at 14q32.31 (GACCGGCTA) and 19p13.2 (AAAC) that conferred significant protection against aortic dilation.
CONCLUSIONS:
These results suggest that consideration of multiple susceptibility signals at these regions identifies individuals in higher risk of aortic dilation or protective against aortic dilation and they may localize regulatory elements at the locus with biological relevance in the pathogenesis of TAAD.


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