Genomic insights in ascending aortic size and distensibility

Benjamins, Jan-Walter; Yeung, Ming Wai; Vegte, Yordi J. van de; Said, M. Abdullah; Linden, Thijs van der; Ties, Daan; Juárez-Orozco, Luis Eduardo; Verweij, Niek

doi:10.1016/j.ebiom.2021.103783

Cited by 30 publications

(33 citation statements)

References 89 publications

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“…In agreement with previous studies, our measurements were significantly larger in men than women, 10,17,18 with increased aortic diameter in men suggested as a reason for the greater incidence of AAA in men. 19 We found that CSA IDPs increased with advancing age, in both men and women.…”

Section: Discussionsupporting

confidence: 93%

“…The strongest association was observed for the thoracic descending aorta, which is perhaps to be expected since this measurement closely corresponds to the location of CMR measurements of the ascending and descending aorta. 10 In agreement with previous studies, our measurements were significantly larger in men than women, 10,17,18 with increased aortic diameter in men suggested as a reason for the greater incidence of AAA in men. 19 We found that CSA IDPs increased with advancing age, in both men and women.…”

Section: Discussionsupporting

confidence: 92%

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Cardiovascular measures from abdominal MRI provide insights into abdominal vessel genetic architecture

Basty

Sorokin

Thanaj

et al. 2022

Preprint

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MRI measurements of heart volumes and vessel dimensions typically require specialised cardiac MRI examinations, which can be time consuming and resource intensive. Simpler scans covering the heart and major blood vessels of the abdomen may potentially provide useful clinical information. We used deep learning to segment cardiovascular structures from UK Biobank (UKBB) abdominal MRI scans and extracted six image-derived phenotypes (heart volume, and cross-sectional areas of the aorta and vena cava at key anatomical locations) from 44,541 participants. We found strong correlations between our measurements and those acquired using conventional cardiac MRI (CMR), with the strength of the association reflecting the degree of anatomical similarity between the measurements. We replicated previous findings related to gender differences and age-related changes in heart and vessel dimensions, and identified a significant association between infrarenal descending aorta cross-sectional area and incident aneurysm, and between heart volume and several cardiovascular disorders. In a genome-wide association study we identified 72 associations at 59 loci, of which 15 had not been previously associated with CMR IDPs. Furthermore, we demonstrated substantial genetic correlation with cardiovascular traits including varicose veins, aneurysms, dysrhythmia and cardiac failure. Our heritability enrichment implicated vascular tissue in the heritability of these traits. We derived a polygenic risk score for each trait and demonstrated an association with aneurysm diagnosis, pointing to a potential screening method for individuals at high-risk of this condition. Our work highlights the rich information content of abdominal MRI and the high degree of overlap with CMR.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Cardiovascular measures from abdominal MRI provide insights into abdominal vessel genetic architecture

Basty

Sorokin

Thanaj

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…We compared our association results for aortic areas with those reported for aortic diameters in recent papers and preprints 30 – 32 based on the same UK Biobank imaging data set, but using different methods and metrics for aortic dimensions (see Supplementary Data 11 ). We replicated 75 of the previously reported genome-wide significant association loci and added associations for clinically relevant phenotypes (ascending and descending aortic distensibility) to identify a further 27 novel associations.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities

et al. 2022

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Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-β, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.

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“…Although genetic variation in TBX20 has been associated with a spectrum of congenital cardiac lesions relating to cardiac and vascular development, 75 there have been increasing observations that genetic loci near TBX20 meet genome wide significance for disease in adulthood including coronary artery disease, 76 myocardial infarction, 77 blood pressure, 78 and aortic dimension and distensibility. 17, 79 Similarly, variants near GATA4 and members of the HOXB family of transcription factors such as HOXB7 have been associated with hypertension, 80, 81 while HAND2 variants are associated with aortic dimension and atrial fibrillation. 17, 82 The vascular bed and cell type specific chromatin accessibility observed in our study of these developmental transcription factors may suggest their ongoing role in mediating vascular disease in adulthood in a vascular bed specific mechanism.…”

Section: Discussionmentioning

confidence: 99%

The epigenomic landscape of single vascular cells reflects developmental origin and identifies disease risk loci

Weldy

Cheng

Pedroza³

et al. 2022

Preprint

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Rationale: Vascular beds have distinct susceptibility to atherosclerosis and aneurysm, yet the biological underpinnings of vascular bed specific disease risk are largely unknown. Vascular tissues have different developmental origins which may influence global chromatin accessibility. Understanding chromatin accessibility and gene expression profiles on single cell resolution is crucial to gain insight into vascular bed specific disease risk. Objective: We aim to understand, on single cell resolution, the global chromatin accessibility and gene expression profiles across distinct vascular beds in the healthy adult mouse to provide insight into the potential mechanisms of vascular bed specific disease risk. Methods and Results: We performed single cell chromatin accessibility (scATACseq) and gene expression profiling (scRNAseq) of healthy adult mouse vascular tissue from three vascular beds, 1) aortic root and ascending aorta, 2) brachiocephalic and carotid artery, and 3) descending thoracic aorta. By integrating datasets and comparing vascular beds within cell type, we identified thousands of differentially accessible chromatin peaks within smooth muscle cells, fibroblasts, and endothelial cells, demonstrating numerous enhancers to be vascular bed specific. We revealed an epigenetic memory of embryonic origin with differential chromatin accessibility of key developmental transcription factors such as Tbx20, Hand2, Gata4, and Hoxb family. Differentially accessible chromatin regions within cell type are also heavily weighted towards genes with known roles in mediating vascular disease risk. Furthermore, cell type specific transcription factor motif accessibility varies by vascular bed, all of which suggest epigenomic profiles as having specific roles in vascular bed specific disease risk. Conclusions: This work supports a paradigm that the epigenomic landscapes of vascular cells are cell type and vascular bed specific and that differentially accessible regions are heavily weighted towards disease risk genes. This work gives insight into vascular bed specific transcriptional and epigenetic programs and highlights the potential for vascular bed specific mechanisms of disease.

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Genomic insights in ascending aortic size and distensibility

Cited by 30 publications

References 89 publications

Cardiovascular measures from abdominal MRI provide insights into abdominal vessel genetic architecture

Cardiovascular measures from abdominal MRI provide insights into abdominal vessel genetic architecture

Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities

The epigenomic landscape of single vascular cells reflects developmental origin and identifies disease risk loci

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