Enrichment of Rare Variants in Loeys–Dietz Syndrome Genes in Spontaneous Coronary Artery Dissection but Not in Severe Fibromuscular Dysplasia

Verstraeten, Aline; Perik, Melanie; Baranowska, Anna A; Meester, Josephina; Heuvel, Lotte Van Den; Bastianen, Jarl; Kempers, Marlies; Krapels, Ingrid P.C.; Maas, Angela H.E.M.; Rideout, Andrea L.; Vandersteen, Anthony; Sobey, Glenda; Johnson, Diana; Fransén, Erik; Ghali, Neeti; Webb, Thomas R.; Al-Hussaini, Abtehale; Leeuw, Peter de; Delmotte, P.; Lopez‐Sublet, Marilucy; Pappaccogli, Marco; Sprynger, Muriel; Toubiana, Laurent; Laer, Lut Van; Dijk, Fleur S van; Vikkula, Miikka; Samani, Nilesh J.; Persu, Alexandre; Adlam, David; Loeys, Bart

doi:10.1161/circulationaha.120.045946

Cited by 37 publications

(36 citation statements)

References 5 publications

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“…The finding of pathogenic variants in COL3A1 , FBN1 , TGFBR1 , TGFBR2 , and PRKG1 , is consistent with previously reported clinical series and cohort studies (Carss et al, 2020; Henkin et al, 2016; Kaadan et al, 2018; Verstraeten et al, 2020). Large cohort studies have found that among individuals with connective tissue disease, SCAD events are rare and sporadic in individuals with MFS, LDS, and vEDS (Eleid et al, 2014; Fattori et al, 2012; Hampole et al, 2011; Henkin et al, 2016; Kaadan et al, 2018; Nakamura et al, 2009; Saw et al, 2014; Sato et al, 2014).…”

Section: Discussionsupporting

confidence: 91%

Spontaneous coronary artery dissection is infrequent in individuals with heritable thoracic aortic disease despite partially shared genetic susceptibility

Murad

Hill

Wang

et al. 2022

American J of Med Genetics Pt A

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Spontaneous coronary artery dissection (SCAD) is a potential precipitant of myocardial infarction and sudden death for which the etiology is poorly understood. Mendelian vascular and connective tissue disorders underlying thoracic aortic disease (TAD), have been reported in ~5% of individuals with SCAD. We therefore hypothesized that patients with TAD are at elevated risk for SCAD. We queried registries enrolling patients with TAD to define the incidence of SCAD. Of 7568 individuals enrolled, 11 (0.15%) were found to have SCAD. Of the sequenced cases (9/11), pathogenic variants were identified (N = 9), including COL3A1 (N = 3), FBN1 (N = 2), TGFBR2 (N = 2), TGFBR1 (N = 1), and PRKG1 (N = 1). Individuals with SCAD had an increased frequency of iliac artery dissection (25.0% vs. 5.1%, p = 0.047). The prevalence of SCAD among individuals with TAD is low. The identification of pathogenic variants in genes previously described in individuals with SCAD, particularly those underlying vascular Ehlers–Danlos, Marfan syndrome, and Loeys–Dietz syndrome, is consistent with prior reports from clinical SCAD series. Further research is needed to identify specific genetic influences on SCAD risk.

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Section: Discussionsupporting

confidence: 91%

Spontaneous coronary artery dissection is infrequent in individuals with heritable thoracic aortic disease despite partially shared genetic susceptibility

Murad

Hill

Wang

et al. 2022

American J of Med Genetics Pt A

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“…The common occurrence of SCAD in young patients without risk factors for atherosclerosis and the identification of cases with familial association have led to the hypothesis of possible genetically mediated pathophysiologic mechanisms. Pathogenic variants were found in COL3A1 ( 8 ), SMAD3 ( 8 , 9 ), TGFBR1/2 , TGFB 2/3 ( 10 ), FBN1 , PHACTR1/EDN1 ( 11 ), TSR1 ( 12 , 13 ), TLN1 ( 14 ), and others ( 14 – 16 ). A recent genome wide association study (GWAS) has identified associations at chromosome 1q21.2 in ADAMTSL4 , chromosome 6p24.1 in PHACTR1 and chromosome 12q13.3 in LRP1 and identified associations of non-coding variants in the LRP1 gene at chromosome 12q13.3 and near MRP6/KCNE3 at chromosome 21q22.11 for SCAD ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Association of Circulating Cathepsin B Levels With Blood Pressure and Aortic Dilation

Chai

Tian

Yang

et al. 2022

Front. Cardiovasc. Med.

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Hypertension is a key risk factor for spontaneous coronary artery dissection (SCAD) and aortic dilation. Circulating proteins play key roles in a range of biological processes and represent a major source of druggable targets. The aim of this study was to identify circulating proteins that were associated with blood pressure (BP), SCAD and aortic dilation. We identified shared genetic variants of BP and SCAD in genome-wide association studies, searched for circulating protein affected by these variants and examined the association of circulating protein levels with BP, aortic aneurysm and dissection (AAD) and aortic diameters by integrating data from circulating protein quantitative trait loci (pQTL) studies and genome wide association study (GWAS) in individuals from the UK Biobank using two-sample Mendelian randomization analysis methods. Single nucleotide polymorphisms (SNPs) in JAG1, ERI1, ULK4, THSD4, CMIP, COL4A2, FBN1, FAM76B, FGGY, NUS1, and HNF4G, which were related to extracellular matrix components, were associated with both BP and SCAD. We found 49 significant pQTL signals among these SNPs. The regulated proteins were encoded by MMP10, IL6R, FIGF, MMP1, CTSB, IGHG1, DSG2, TTC17, RETN, POMC, SCARF2, RELT, and GALNT16, which were enriched in biological processes such as collagen metabolic process and multicellular organism metabolic process. Causal associations between BP and AAD and aortic diameters were detected. Significant associations between circulating levels of cathepsin B, a well-known prorenin processing enzyme, and BP and aortic diameters were identified by using several Mendelian randomization analysis methods and were validated by independent data.ConclusionThe present study identified the association between circulating cathepsin B and BP and aortic diameters. The findings indicated that BP-associated genetic variants may influence aortic dilation risk by circulating proteins that regulate BP.

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“…Arterial disease beyond the ascending aorta seems less frequent, with an extension of thoracic aortic aneurysm into the brachiocephalic artery, one hepatic arterial aneurysm and only one patient displaying aneurysm throughout the body in literature [4,7]. We were the first to report spontaneous coronary artery dissection as part of the LOX phenotype [9]. We observed no difference between premature stop codon LOX variants (n = 23) and missense LOX variants (n = 22) with regards to median age of diagnosis (47.5 years versus 44 years) or severity of the cardiovascular involvement.…”

Section: Discussionmentioning

confidence: 87%

Novel LOX Variants in Five Families with Aortic/Arterial Aneurysm and Dissection with Variable Connective Tissue Findings

Gucht

Krebsová

Diness

et al. 2021

IJMS

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Thoracic aortic aneurysm and dissection (TAAD) is a major cause of cardiovascular morbidity and mortality. Loss-of-function variants in LOX, encoding the extracellular matrix crosslinking enzyme lysyl oxidase, have been reported to cause familial TAAD. Using a next-generation TAAD gene panel, we identified five additional probands carrying LOX variants, including two missense variants affecting highly conserved amino acids in the LOX catalytic domain and three truncating variants. Connective tissue manifestations are apparent in a substantial fraction of the variant carriers. Some LOX variant carriers presented with TAAD early in life, while others had normal aortic diameters at an advanced age. Finally, we identified the first patient with spontaneous coronary artery dissection carrying a LOX variant. In conclusion, our data demonstrate that loss-of-function LOX variants cause a spectrum of aortic and arterial aneurysmal disease, often combined with connective tissue findings.

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Enrichment of Rare Variants in Loeys–Dietz Syndrome Genes in Spontaneous Coronary Artery Dissection but Not in Severe Fibromuscular Dysplasia

Cited by 37 publications

References 5 publications

Spontaneous coronary artery dissection is infrequent in individuals with heritable thoracic aortic disease despite partially shared genetic susceptibility

Spontaneous coronary artery dissection is infrequent in individuals with heritable thoracic aortic disease despite partially shared genetic susceptibility

Association of Circulating Cathepsin B Levels With Blood Pressure and Aortic Dilation

Novel LOX Variants in Five Families with Aortic/Arterial Aneurysm and Dissection with Variable Connective Tissue Findings

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