BACKGROUND: Bicuspid aortic valve (BAV) disease is a congenital defect that affects 0.5% to 1.2% of the population and is associated with comorbidities including ascending aortic dilation and calcific aortic valve stenosis. To date, although a few causal genes have been identified, the genetic basis for the vast majority of BAV cases remains unknown, likely pointing to complex genetic heterogeneity underlying this phenotype. Identifying genetic pathways versus individual gene variants may provide an avenue for uncovering additional BAV causes and consequent comorbidities. METHODS: We performed genome-wide association Discovery and Replication Studies using cohorts of 2131 patients with BAV and 2728 control patients, respectively, which identified primary cilia genes as associated with the BAV phenotype. Genome-wide association study hits were prioritized based on P value and validated through in vivo loss of function and rescue experiments, 3-dimensional immunohistochemistry, histology, and morphometric analyses during aortic valve morphogenesis and in aged animals in multiple species. Consequences of these genetic perturbations on cilia-dependent pathways were analyzed by Western and immunohistochemistry analyses, and assessment of aortic valve and cardiac function were determined by echocardiography. RESULTS: Genome-wide association study hits revealed an association between BAV and genetic variation in human primary cilia. The most associated single-nucleotide polymorphisms were identified in or near genes that are important in regulating ciliogenesis through the exocyst, a shuttling complex that chaperones cilia cargo to the membrane. Genetic dismantling of the exocyst resulted in impaired ciliogenesis, disrupted ciliogenic signaling and a spectrum of cardiac defects in zebrafish, and aortic valve defects including BAV, valvular stenosis, and valvular calcification in murine models. CONCLUSIONS: These data support the exocyst as required for normal ciliogenesis during aortic valve morphogenesis and implicate disruption of ciliogenesis and its downstream pathways as contributory to BAV and associated comorbidities in humans.
Bibliographical noteFunding Information:
This work was supported in part by grants from the Veterans Affairs (Merit Award I01 BX000820 to Dr Lipschutz), National Institutes of Health (GM103444 to Dr Norris; P30DK074038 to Dr Lipschutz; R21EY025034 to Dr Lobo; R01HL131546, P20GM103444, and R01HL127692 to Dr Norris; K01DK087852 and P20GM103457-8293 to Dr Fogelgren; T32HL007260 to D. Fulmer and K. Moore; F31HL142159 to D. Fulmer; and R01GM122078 and R21CA209848 to Dr Chung), Dialysis Clinic, Inc. (to J.H.L.), and American Heart Association (17CSA33590067 to Drs Norris, Body, and Lipschutz, and 18PRE34080172 to Dr Guo).
© 2019 American Heart Association, Inc.
- Aortic valve
- Aortic valve stenosis
- Bicuspid aortic valve
- EXOC5 protein, human