Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2018 Update and Clinical Implications.
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SUBMITTER: Brownstein AJ
PROVIDER: S-EPMC6136681 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
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Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2018 Update and Clinical Implications.
Brownstein Adam J AJ Kostiuk Valentyna V Ziganshin Bulat A BA Zafar Mohammad A MA Kuivaniemi Helena H Body Simon C SC Bale Allen E AE Elefteriades John A JA
Aorta (Stamford, Conn.) 20180201 1
Thoracic aortic aneurysms, with an estimated prevalence in the general population of 1%, are potentially lethal, via rupture or dissection. Over the prior two decades, there has been an exponential increase in our understanding of the genetics of thoracic aortic aneurysm and/or dissection (TAAD). To date, 30 genes have been shown to be associated with the development of TAAD and ∼30% of individuals with nonsyndromic familial TAAD have a pathogenic mutation in one of these genes. This review repr ...[more]
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Project description:Thoracic aortic aneurysm is a typically silent disease characterized by a lethal natural history. Since the discovery of the familial nature of thoracic aortic aneurysm and dissection (TAAD) almost 2 decades ago, our understanding of the genetics of this disorder has undergone a transformative amplification. To date, at least 37 TAAD-causing genes have been identified and an estimated 30% of the patients with familial nonsyndromic TAAD harbor a pathogenic mutation in one of these genes. In this review, we present our yearly update summarizing the genes associated with TAAD and the ensuing clinical implications for surgical intervention. Molecular genetics will continue to bolster this burgeoning catalog of culprit genes, enabling the provision of personalized aortic care.
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Project description:Thoracic aortic aneurysm (TAA) is a lethal disease, with a natural history of enlarging progressively until dissection or rupture occurs. Since the discovery almost 20 years ago that ascending TAAs are highly familial, our understanding of the genetics of thoracic aortic aneurysm and dissection (TAAD) has increased exponentially. At least 29 genes have been shown to be associated with the development of TAAD, the majority of which encode proteins involved in the extracellular matrix, smooth muscle cell contraction or metabolism, or the transforming growth factor-β signaling pathway. Almost one-quarter of TAAD patients have a mutation in one of these genes. In this review, we provide a summary of TAAD-associated genes, associated clinical features of the vasculature, and implications for surgical treatment of TAAD. With the widespread use of next-generation sequencing and development of novel functional assays, the future of the genetics of TAAD is bright, as both novel TAAD genes and variants within the genes will continue to be identified.
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Project description:BACKGROUND:Thoracic aortic aneurysms progressively enlarge and predispose to acute aortic dissections. Up to 25% of individuals with thoracic aortic disease harbor an underlying Mendelian pathogenic variant. An evidence-based strategy for selection of genes to test in hereditary thoracic aortic aneurysm and dissection (HTAAD) helps inform family screening and intervention to prevent life-threatening thoracic aortic events. OBJECTIVES:The purpose of this study was to accurately identify genes that predispose to HTAAD using the Clinical Genome Resource (ClinGen) framework. METHODS:We applied the semiquantitative ClinGen framework to assess presumed gene-disease relationships between 53 candidate genes and HTAAD. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable, triggering routine aortic surveillance, intervention, and family cascade screening. All gene-disease assertions were evaluated by a pre-defined curator-expert pair and subsequently discussed with an expert panel. RESULTS:Genes were classified based on the strength of association with HTAAD into 5 categories: definitive (n = 9), strong (n = 2), moderate (n = 4), limited (n = 15), and no reported evidence (n = 23). They were further categorized by severity of associated aortic disease and risk of progression. Eleven genes in the definitive and strong groups were designated as "HTAAD genes" (category A). Eight genes were classified as unlikely to be progressive (category B) and 4 as low risk (category C). The remaining genes were recent genes with an uncertain classification or genes with no evidence of association with HTAAD. CONCLUSIONS:The ClinGen framework is useful to semiquantitatively assess the strength of gene-disease relationships for HTAAD. Gene categories resulting from the curation may inform clinical laboratories in the development, interpretation, and subsequent clinical implications of genetic testing for patients with aortic disease.
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Project description:AimsThoracic aortic aneurysm/dissection (TAAD) is a life-threatening disease with diverse clinical manifestations. Although the association between methamphetamine (METH) and TAAD is frequently observed, the causal relationship between METH abuse and aortic aneurysm/dissection has not been established. This study was designed to determine if METH causes aortic aneurysm/dissection and delineate the underlying mechanism.Methods and resultsA new TAAD model was developed by exposing METH to SD rats pre-treated with lysyl oxidase inhibitor β-aminopropionitrile (BAPN). Combination of METH and BAPN caused thoracic aortic aneurysm/dissection in 60% of rats. BAPN+METH significantly increased the expression and activities of both matrix metalloproteinase MMP2 and MMP9, consistent with the severe elastin breakage and dissection. Mechanistically, METH increased CCAAT-enhancer binding protein β (C/EBPβ) expression by enhancing mothers against decapentaplegic homolog 3 (Smad3) and extracellular regulated protein kinase (ERK1/2) signaling. METH also promoted C/EBPβ binding to MMP2 and MMP9 promoters. Blocking C/EBPβ significantly attenuated METH+BAPN-induced TAAD and MMP2/MMP9 expression. Moreover, BAPN+METH promoted aortic medial smooth muscle cell (SMC) apoptosis through C/EBPβ-mediated IGFBP5/p53/PUMA signaling pathways. More importantly, the expression of C/EBPβ, MMP2/MMP9, and apoptosis-promoting proteins was increased in the aorta of human patients with thoracic aortic dissection, suggesting that the mechanisms identified in animal study could be relevant to human disease.ConclusionsOur study demonstrated that METH exposure has a casual effect on TAAD. C/EBPβ mediates METH-introduced TAAD formation by causing elastin breakage, medial cell loss and degeneration. Therefore, C/EBPβ may be a potential factor for TAAD clinical diagnosis or treatment.
| S-EPMC9753351 | biostudies-literature
Project description:BackgroundThoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members.MethodsWe performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity.ResultsTwenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age <50 (odds ratio [OR], 5.5; 95% CI, 1.6-19.7), no history of hypertension (OR, 5.6; 95% CI, 1.4-22.3), and family history of aortic disease (mother: OR, 5.7; 95% CI, 1.4-22.3, siblings: OR, 5.1; 95% CI, 1.1-23.9, children: OR, 6.0; 95% CI, 1.4-26.7).ConclusionsClinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.
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Project description:Proteoglycan accumulation is a hallmark of medial degeneration in thoracic aortic aneurysm and dissection (TAAD). Here, we defined the aortic proteoglycanome using mass spectrometry, and based on the findings, investigated the large aggregating proteoglycans aggrecan and versican in human ascending TAAD and a mouse model of severe Marfan syndrome. The aortic proteoglycanome comprises 20 proteoglycans including aggrecan and versican. Antibodies against these proteoglycans intensely stained medial degeneration lesions in TAAD, contrasting with modest intralamellar staining in controls. Aggrecan, but not versican, was increased in longitudinal analysis of Fbn1mgR/mgR aortas. TAAD and Fbn1mgR/mgR aortas had increased aggrecan and versican mRNAs, and reduced expression of a key proteoglycanase gene, ADAMTS5, was seen in TAAD. Fbn1mgR/mgR mice with ascending aortic dissection and/or rupture had dramatically increased aggrecan staining compared with mice without these complications. Thus, aggrecan and versican accumulation in ascending TAAD occurs via increased synthesis and/or reduced proteolytic turnover, and correlates with aortic dissection/rupture in Fbn1mgR/mgR mice. Tissue swelling imposed by aggrecan and versican is proposed to be profoundly deleterious to aortic wall mechanics and smooth muscle cell homeostasis, predisposing to type-A dissections. These proteoglycans provide potential biomarkers for refined risk stratification and timing of elective aortic aneurysm repair.
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Project description:A recent genome wide association study (GWAS) by LeMaire et al. found that two single nucleotide polymorphisms (SNPs), rs2118181 and rs10519177 in the FBN-1 gene (encoding Fibrillin-1), were associated with thoracic aortic dissection (TAD), non-dissecting thoracic aortic aneurysm (TAA), and thoracic aortic aneurysm or dissection (TAAD); the largest effect was observed for the association of rs2118181 with TAD. We investigated whether rs2118181 and rs10519177 were associated with TAD, TAA, and TAAD in the Yale study.The genotypes of rs2118181 and rs10519177 were determined for participants in the Yale study: 637 TAAD cases (140 TAD, 497 TAA) and 275 controls from the United States, Hungary, and Greece. The association of the genotypes with TAD, TAA and TAAD were assessed using logistic regression models adjusted for sex, age, study center and hypertension.In the Yale study, rs2118181 was associated with TAD: compared with non-carriers, carriers of the risk allele had an unadjusted odds ratio for TAD of 1.80 (95% CI 1.15-2.80) and they had odds ratio for TAD of 1.87 (95% CI 1.09-3.20) after adjusting for sex, age, study center and hypertension. We did not find significant differences in aortic size, a potential confounder for TAD, between rs2118181 risk variant carriers and non-carriers: mean aortic size was 5.56 (95% CI: 5.37-5.73) for risk variant carriers (CC+CT) and was 5.48 (95% CI: 5.36-5.61) for noncarriers (TT) (p?=?0.56). rs2118181 was not associated with TAA or TAAD. rs10519177 was not associated with TAD, TAA, or TAAD in the Yale study. Thus, the Yale study provided further support for the association of the FBN-1 rs2118181SNP with TAD.
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