Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program

Klarin, Derek; Devineni, Poornima; Sendamarai, Anoop K.; Angueira, Anthony R.; Graham, Sarah E.; Shen, Ying H.; Levin, Michael G.; Surakka, Ida; Karnam, Purushotham; Roychowdhury, Tanmoy; Li, Yanming; Wang, Minxian; Aragam, Krishna; Paruchuri, Kaavya; Zuber, Verena; Shakt, Gabrielle; Tsao, Noah; Judy, Renae; Vy, Ha My T.; Verma, Shefali S.; Rader, Daniel J.; Do, Ron; Bavaria, Joseph E.; Nadkarni, Girish N.; Ritchie, Marylyn D.; Burgess, Stephen; Guo, Dongchuan; Ellinor, Patrick T.; LeMaire, Scott A.; Milewicz, Dianna M.; Willer, Cristen J.; Natarajan, Pradeep; Tsao, Phil; Pyarajan, Saiju; Damrauer, Scott M.

doi:10.1038/s41588-023-01420-z

Cited by 21 publications

(16 citation statements)

References 67 publications

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“…Interestingly, the ascending aorta seems more influenced by diabetes and glycemic traits than the descending aorta. Previous research indicated that the vascular smooth muscle cells of the thoracic ascending aorta have a distinct embryonic origin from the rest of the arterial tree, arising from neural crest cells [ 40 ]. Given that, we theorize that the ascending thoracic aorta may be more susceptible to diabetes and disruptions in glycemic balance.…”

Section: Discussionmentioning

confidence: 99%

Effects of diabetes mellitus and glycemic traits on cardiovascular morpho-functional phenotypes

Li,

Xiong,

Guo

et al. 2023

Cardiovasc Diabetol

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Background The effects of diabetes on the cardiac and aortic structure and function remain unclear. Detecting and intervening these variations early is crucial for the prevention and management of complications. Cardiovascular magnetic resonance imaging-derived traits are established endophenotypes and serve as precise, early-detection, noninvasive clinical risk biomarkers. We conducted a Mendelian randomization (MR) study to examine the association between two types of diabetes, four glycemic traits, and preclinical endophenotypes of cardiac and aortic structure and function. Methods Independent genetic variants significantly associated with type 1 diabetes, type 2 diabetes, fasting insulin (FIns), fasting glucose (FGlu), 2 h-glucose post-challenge (2hGlu), and glycated hemoglobin (HbA1c) were selected as instrumental variables. The 96 cardiovascular magnetic resonance imaging traits came from six independent genome-wide association studies. These traits serve as preclinical endophenotypes and offer an early indication of the structure and function of the four cardiac chambers and two aortic sections. The primary analysis was performed using MR with the inverse-variance weighted method. Confirmation was achieved through Steiger filtering and testing to determine the causal direction. Sensitivity analyses were conducted using the weighted median, MR-Egger, and MR-PRESSO methods. Additionally, multivariable MR was used to adjust for potential effects associated with body mass index. Results Genetic susceptibility to type 1 diabetes was associated with increased ascending aortic distensibility. Conversely, type 2 diabetes showed a correlation with a reduced diameter and areas of the ascending aorta, as well as decreased distensibility of the descending aorta. Genetically predicted higher levels of FGlu and HbA1c were correlated with a decrease in diameter and areas of the ascending aorta. Furthermore, higher 2hGlu levels predominantly showed association with a reduced diameter of both the ascending and descending aorta. Higher FIns levels corresponded to increased regional myocardial-wall thicknesses at end-diastole, global myocardial-wall thickness at end-diastole, and regional peak circumferential strain of the left ventricle. Conclusions This study provides evidence that diabetes and glycemic traits have a causal relationship with cardiac and aortic structural and functional remodeling, highlighting the importance of intensive glucose-lowering for primary prevention of cardiovascular diseases.

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Section: Discussionmentioning

confidence: 99%

Effects of diabetes mellitus and glycemic traits on cardiovascular morpho-functional phenotypes

Li,

Xiong,

Guo

et al. 2023

Cardiovasc Diabetol

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“…On the other hand, it cannot be excluded that the early-onset cases, including those described by Van Gucht et al [24] and Guo et al [23], are caused by additional genetic defects that have not been found. Indeed, there are reports suggesting the role of digenic/oligogenic/polygenic inheritance in TAA [33][34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Double Heterozygous Pathogenic Variants in the LOX and PKD1 Genes in a 5-Year-Old Patient with Thoracic Aortic Aneurysm and Polycystic Kidney Disease

Ponińska,

Pelczar-Płachta,

Pollak

et al. 2023

Genes

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Familial thoracic aortic aneurysms and dissections may occur as an isolated hereditary trait or as part of connective tissue disorders with Mendelian inheritance, but severe cardiovascular disease in pediatric patients is extremely rare. There is growing knowledge on pathogenic variants causing the disease; however, much of the phenotypic variability and gene–gene interactions remain to be discovered. We present a case report of a 5.5-year-old girl with an aortic aneurysm and concomitant polycystic kidney disease. Whole exome sequencing was performed, followed by family screening by amplicon deep sequencing and diagnostic imaging studies. In the proband, two pathogenic variants were identified: p.Tyr257Ter in the LOX gene inherited from her mother, and p.Thr2977Ile in the PKD1 gene inherited from her father. All adult carriers of either of these variants showed symptoms of aortic disease. We conclude that the coexistence of two independent genetic variants in the proband may be the reason for an early onset of disease.

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“…Follow-up in vitro studies suggested that upregulation of TCF7L2 , which encodes a transcription factor in the Wnt (wingless-related integration site)/β-catenin pathway, leads to BCL2 repression and thus increased VSMC apoptosis. Most recently, Klarin et al 14 published a GWAS of 8626 individuals with TAAD in the Million Veteran Program, with replication in 6 external cohorts, and identified 21 TAAD risk loci. Genome-wide copy number variation analyses have identified an enrichment of copy number variation regions in sporadic TAAD cases, although none of these individual associations achieved statistical significance.…”

Section: Gwas For Aortic Traitsmentioning

confidence: 99%

Using Genomics to Identify Novel Therapeutic Targets for Aortic Disease

Raghavan,

Pirruccello,

Ellinor

et al. 2024

ATVB

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Aortic disease, including dissection, aneurysm, and rupture, carries significant morbidity and mortality and is a notable cause of sudden cardiac death. Much of our knowledge regarding the genetic basis of aortic disease has relied on the study of individuals with Mendelian aortopathies and, until recently, the genetic determinants of population-level variance in aortic phenotypes remained unclear. However, the application of machine learning methodologies to large imaging datasets has enabled researchers to rapidly define aortic traits and mine dozens of novel genetic associations for phenotypes such as aortic diameter and distensibility. In this review, we highlight the emerging potential of genomics for identifying causal genes and candidate drug targets for aortic disease. We describe how deep learning technologies have accelerated the pace of genetic discovery in this field. We then provide a blueprint for translating genetic associations to biological insights, reviewing techniques for locus and cell type prioritization, high-throughput functional screening, and disease modeling using cellular and animal models of aortic disease.

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Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program

Cited by 21 publications

References 67 publications

Effects of diabetes mellitus and glycemic traits on cardiovascular morpho-functional phenotypes

Effects of diabetes mellitus and glycemic traits on cardiovascular morpho-functional phenotypes

Double Heterozygous Pathogenic Variants in the LOX and PKD1 Genes in a 5-Year-Old Patient with Thoracic Aortic Aneurysm and Polycystic Kidney Disease

Using Genomics to Identify Novel Therapeutic Targets for Aortic Disease

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