Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection.
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ABSTRACT:
SUBMITTER: Debette S
PROVIDER: S-EPMC5824623 | biostudies-literature | 2015 Jan
REPOSITORIES: biostudies-literature
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Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection.
Debette Stéphanie S Kamatani Yoichiro Y Metso Tiina M TM Kloss Manja M Chauhan Ganesh G Engelter Stefan T ST Pezzini Alessandro A Thijs Vincent V Markus Hugh S HS Dichgans Martin M Wolf Christiane C Dittrich Ralf R Touzé Emmanuel E Southerland Andrew M AM Samson Yves Y Abboud Shérine S Béjot Yannick Y Caso Valeria V Bersano Anna A Gschwendtner Andreas A Sessa Maria M Cole John J Lamy Chantal C Medeiros Elisabeth E Beretta Simone S Bonati Leo H LH Grau Armin J AJ Michel Patrik P Majersik Jennifer J JJ Sharma Pankaj P Kalashnikova Ludmila L Nazarova Maria M Dobrynina Larisa L Bartels Eva E Guillon Benoit B van den Herik Evita G EG Fernandez-Cadenas Israel I Jood Katarina K Nalls Michael A MA De Leeuw Frank-Erik FE Jern Christina C Cheng Yu-Ching YC Werner Inge I Metso Antti J AJ Lichy Christoph C Lyrer Philippe A PA Brandt Tobias T Boncoraglio Giorgio B GB Wichmann Heinz-Erich HE Gieger Christian C Johnson Andrew D AD Böttcher Thomas T Castellano Maurizio M Arveiler Dominique D Ikram M Arfan MA Breteler Monique M B MM Padovani Alessandro A Meschia James F JF Kuhlenbäumer Gregor G Rolfs Arndt A Worrall Bradford B BB Ringelstein Erich-Bernd EB Zelenika Diana D Tatlisumak Turgut T Lathrop Mark M Leys Didier D Amouyel Philippe P Dallongeville Jean J
Nature genetics 20141124 1
Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We per ...[more]
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Project description:Cervical artery dissection (CeAD) occurs in healthy young individuals and often entails ischemic stroke. Skin biopsies from most CeAD-patients show minor connective tissue alterations. We search for rare genetic deletions and duplication that may predispose to CeAD. Forty-nine non-traumatic CeAD-patients with electron microscopic (EM) alterations of their dermal connective tissue (EM+ patients) and 21 patients with normal connective tissue in skin biopsies (EM- patients) were analyzed. Affymetrix 6.0 microarrays (Affymetrix) from all patients were screened for copy number variants (CNVs). CNVs absent from 403 control subjects and from 2402 published disease-free individuals were considered as CeAD-associated. The genetic content of undentified CNVs was analyzed by means of the Gene Ontology (GO) Term Mapper to detect associations with biological processes. In 49 EM+ patients we identified 13 CeAD-associated CNVs harboring 83 protein-coding genes. In 21 EM- patients we found five CeAD-associated CNVs containing only nine genes (comparison of CNV gene density between the groups: Mann-Whitney P=0.039). Patients' CNVs were enriched for genes involved in extracellular matrix organization (COL5A2, COL3A1, SNTA1, P=0.035), collagen fibril organization COL5A2, COL3A1, (P=0.0001) and possibly for genes involved in transforming growth factor beta (TGF)-beta receptor signaling pathway (COL3A1, DUPS22, P=0.068). We conclude that rare genetic variants may contribute to the pathogenesis of CeAD, in particular in patients with a microscopic connective tissue phenotype.
| S-EPMC3499738 | biostudies-literature
Project description:Background Cervical artery dissection (CeAD) is a frequent manifestation of fibromuscular dysplasia (FMD). However, risk factors for CeAD are unknown. We investigated factors associated with CeAD in the ARCADIA (Assessment of Renal and Cervical Artery Dysplasia) registry. Methods and Results The ARCADIA registry includes women or men aged ≥18 years, with a diagnosis of renal, cervical, or intracranial artery FMD, who were prospectively recruited at 16 university hospitals in France and Belgium. Diagnosis of acute or past CeAD at inclusion was established on imaging according to standard diagnostic criteria. Associations between potential determinants and CeAD were assessed by logistic regression analyses. Among 469 patients (75 men) with FMD, 65 (13.9%) had CeAD. Patients with CeAD were younger, more likely to be men, have a history of migraine, and less likely to have a history of hypertension than patients without CeAD. In the multivariable analysis, male sex (odds ratio [OR], 2.66; 95% CI, 1.34-5.25), history of migraine (OR, 1.90; 95% CI, 1.06-3.39), age ≥50 years (OR, 0.41; 95% CI, 0.23-0.73), history of hypertension (OR, 0.35; 95% CI, 0.20-0.64), and involvement of ≥3 vascular beds (OR, 2.49; 95% CI, 1.15-5.40) were significantly associated with CeAD. To validate the association between CeAD and sex, we performed a systematic review. We collected additional data on sex from 2 published studies and unpublished data from the US Registry for Fibromuscular Dysplasia and the European/International FMD Registry. In the pooled analysis (289 CeAD, 1933 patients), male sex was significantly associated with CeAD (OR, 2.04; 95% CI, 1.41-2.95; I2=0%). Conclusions In patients with FMD, male sex and multisite involvement are associated with CeAD, in addition to other previously known risk factors. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02884141.
| S-EPMC8483547 | biostudies-literature
Project description:BackgroundGenetic and environmental risk factors are assumed to contribute to the susceptibility to cervical artery dissection (CeAD). To explore the role of genetic imbalance in the etiology of CeAD, copy number variants (CNVs) were identified in high-density microarrays samples from the multicenter CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study and from control subjects from the CADISP study and the German PopGen biobank. Microarray data from 833 CeAD patients and 2040 control subjects (565 subjects with ischemic stroke due to causes different from CeAD and 1475 disease-free individuals) were analyzed. Rare genic CNVs were equally frequent in CeAD-patients (16.4%; n=137) and in control subjects (17.0%; n=346) but differed with respect to their genetic content. Compared to control subjects, CNVs from CeAD patients were enriched for genes associated with muscle organ development and cell differentiation, which suggests a possible association with arterial development. CNVs affecting cardiovascular system development were more common in CeAD patients than in control subjects (p=0.003; odds ratio (OR) =2.5; 95% confidence interval (95% CI) =1.4-4.5) and more common in patients with a familial history of CeAD than in those with sporadic CeAD (p=0.036; OR=11.2; 95% CI=1.2-107).ConclusionThe findings suggest that rare genetic imbalance affecting cardiovascular system development may contribute to the risk of CeAD. Validation of these findings in independent study populations is warranted.
| S-EPMC5345335 | biostudies-literature
Project description:ImportanceExtracranial carotid and vertebral artery dissection is an important cause of stroke, particularly in younger individuals. In some but not all observational studies, it has been associated with a high risk of recurrent stroke. Both antiplatelet agents (APs) and anticoagulants (ACs) are used to reduce stroke risk, but whether 1 treatment strategy is more effective is unknown.ObjectiveTo determine whether AP or AC therapy is more effective in preventing stroke in cervical dissection and the risk of recurrent stroke in a randomized clinical trial setting. A secondary outcome was to determine the effect on arterial imaging outcomes.Design, setting, and participantsRandomized, prospective, open-label international multicenter parallel design study with central blinded review of both clinical and imaging end points. Recruitment was conducted in 39 stroke and neurology secondary care centers in the United Kingdom and 7 centers in Australia between February 24, 2006, and June 17, 2013. One-year follow-up and analysis was conducted in 2018. Two hundred fifty participants with extracranial carotid and vertebral dissection with symptom onset within the last 7 days were recruited. Follow-up data at 1 year were available for all participants.InterventionsRandomization to AP or AC (heparin followed by warfarin) for 3 months, after which the choice of AP and AC agents was decided by the local clinician.Main outcomes and measuresThe primary end point was ipsilateral stroke and death. A planned per protocol (PP) analysis was performed in patients meeting the inclusion criteria following central review of imaging to confirm the diagnosis of dissection. A secondary end point was angiographic recanalization in those with imaging confirmed dissection.ResultsTwo hundred fifty patients were randomized (118 carotid and 132 vertebral), 126 to AP and 124 to AC. Mean (SD) age was 49 (12) years. Mean (SD) time to randomization was 3.65 (1.91) days. The recurrent stroke rate at 1 year was 6 of 250 (2.4%) on ITT analysis and 5 of 197 (2.5%) on PP analysis. There were no significant differences between treatment groups for any outcome. Of the 181 patients with confirmed dissection and complete imaging at baseline and 3 months, there was no difference in the presence of residual narrowing or occlusion between those receiving AP (n = 56 of 92) vs those receiving AC (n = 53 of 89) (P = .97).Conclusions and relevanceDuring 12 months of follow-up, the number of recurrent strokes was low. There was no difference between treatment groups in outcome events or the rate of recanalization.Trial registrationISRCTN.com Identifier: CTN44555237.
| S-EPMC6563567 | biostudies-literature
Project description:Cervical artery dissection (CAD) is a frequent cause of stroke in young adults. Previous studies investigating the efficiency of anticoagulation (AC) versus antiplatelet therapy (AT) found an insignificant difference. We therefore retrospectively evaluated a combination of AC plus AT in patients with acute CAD regarding safety and efficacy. Twenty-eight patients with CAD and minor neurological symptoms/no major infarction received either single (n = 14) or dual AT (n = 14) combined with AC. Angiographic follow-up during hospitalization, 4-8 weeks and 3-6 months after CAD focused on occlusion, residual stenosis, and functional recanalization. Possible adverse events were surveyed. We compared the AC plus AT group to 22 patients with acute CAD treated with AC or AT. Compared to preceding AC-/AT-only studies, AC plus single or dual AT resulted in more frequent, faster recanalization. Frequency and severity of adverse events was comparable. No major adverse events or death occurred. Preceding works on conservative treatment of CAD are discussed and compared to this study. Considerations are given to pathophysiology and the dynamic of CAD. Combining AC plus AT in CAD may result in more reliable recanalization in a shorter time. The risk for adverse events appears similar to treatment with only AC or AT.
| S-EPMC8509613 | biostudies-literature
Project description:IntroductionThe potential role of genetic alterations in cervical artery dissection (CeAD) pathogenesis is poorly understood. We aimed to identify pathogenic genetic variants associated with cervical artery dissection by using whole exome sequencing.Patients and methodsCeAD-patients with either a family history of cervical artery dissection (f-CeAD) or recurrent cervical artery dissection (r-CeAD) from the CeAD-databases of two experienced stroke centres were analysed by whole exome sequencing.Variants with allele frequency <0.05 and classified as pathogenic by predicting algorithms (SIFT or Polyphen-2) or the ClinVar database were explored. First, we analysed a panel of 30 candidate genes associated with arterial dissection (any site) or aneurysm according to the OMIM (online Mendelian Inheritance of Men) database. Second, we performed a genome-wide search for pathogenic variants causing other vascular phenotypes possibly related to cervical artery dissection.Findings were classified as CeAD-causing (pathogenic variants in genes from the arterial dissection or aneurysm panel) or suggestive (pathogenic variants in genes associated with other vascular phenotypes and variants of unknown significance in genes from the arterial dissection or aneurysm panel). All other variants were classified as benign/uncertain.ResultsAmong 43 CeAD-patients, 28 patients (17 pedigrees) had f-CeAD and 15 had r-CeAD. No CeAD-causing variants were identified in r-CeAD patients. Among f-CeAD-patients, 5/17 pedigrees carried CeAD-causing variants in COL3A1, COL4A1, COL4A3, COL4A4, COL5A1, COL5A2 and FBN1. Suggestive variants in ABCC6, COL3A1, COL5A2, MEF2A, and RNF213 were detected in three pedigrees with f-CeAD and six patients with r-CeAD.Discussion and conclusion: CeAD-causing variants were rare and exclusively found in f-CeAD-patients, suggesting differences between the genetic architectures of f-CeAD and r-CeAD. The identified variants indicate a high genetic heterogeneity of the study sample.
| S-EPMC6921947 | biostudies-literature
Project description:Common carotid artery dissection is an unusual clinical event that most commonly occurs secondary to type A aortic dissection. We present a rare case of spontaneous common carotid artery dissection temporally preceding aortic dissection. Our case highlights the careful attention that cases of common carotid dissection should be given; our knowledge base regarding their natural history and evidence-based management is distinctly lacking compared to dissection of other cervical vessels. It also demonstrates the importance of imaging the entire aorta at the time of, a seemingly isolated, common carotid dissection to exclude other potential synchronous dissections.
| S-EPMC6429546 | biostudies-literature
Project description:The common femoral artery is the most frequently used access site for angiographic procedures in interventional radiology. Potential complications of common femoral arteriotomy include hematoma formation, pseudoaneurysm, uncontrolled groin or retroperitoneal bleeding, acute arterial occlusion, dissection, and arteriovenous fistula formation. In a case such as the one described here, with a common femoral artery dissection with intraluminal thrombus and vessel occlusion, the complication may have occurred at the time of access or at the time of closure, with both procedure-associated and patient-specific risk factors affecting the overall risk of complications. Though some studies have shown an increased risk of complications with the use of arterial closure devices, others have found no increase. In any patient with symptoms following a femoral arteriotomy, rapid diagnosis and treatment is necessary to avoid further complications. Both patient-specific and procedure-associated risk factors should be considered prior to arteriotomy and usage of an arterial closure device.
| S-EPMC3193314 | biostudies-other
Project description:ObjectiveTo investigate the prevalence of connective tissue abnormalities in patients with spontaneous cervical artery dissections (sCeAD).MethodsWe systematically assessed clinically detectable signs of connective tissue aberration in a series of consecutive patients with sCeAD and of age- and sex-matched patients with ischemic stroke unrelated to CeAD (non-CeAD IS) by a standard examination protocol including 68 items, and performed extensive molecular investigation for hereditary connective tissue disorders in all patients with sCeAD.ResultsThe study group included 84 patients with sCeAD (mean age, 44.5 ± 7.8 years; 66.7% men) and 84 patients with non-CeAD IS. None of the patients with sCeAD met clinical or molecular diagnostic criteria for established hereditary connective tissue disorder. Connective tissue abnormalities were detected more frequently in the group of patients with sCeAD than in the group of those with non-CeAD IS (mean number of pathologic findings, 4.5 ± 3.5 vs 1.9 ± 2.3; p < 0.001). Eighty-one patients (96.4%) in the sCeAD group had at least one detectable sign compared with 55 patients (66.7%) in the group with non-CeAD IS (p < 0.001). Skeletal, ocular, and skin abnormalities, as well as craniofacial dysmorphisms, were the clinical signs more strongly associated with sCeAD. Signs suggesting connective tissue abnormality were also more frequently represented in patients with sCeAD than in patients with traumatic CeAD (28.6%, p < 0.001; mean number of pathologic findings, 1.7 ± 3.7, p = 0.045).ConclusionsConnective tissue abnormalities are frequent in patients with sCeAD. This reinforces the hypothesis that systemic aberrations of the connective tissue might be implicated in the pathogenesis of the disease.
| S-EPMC4248452 | biostudies-literature
Project description:IntroductionCervical artery dissection, including carotid and vertebral artery dissection, is an important cause of stroke in the young. Risk of developing cervical artery dissection has been associated with physical activity in various forms and has been presumed to be related to minor trauma and mechanical stretching of the cervical arteries. This systematic review will aim to synthesise data on the risk of recurrent cervical artery dissection after an initial dissection. This information may be applied to further understand the natural history of this disease, and potentially to help direct evidence-based discussions on safe return to activity after dissection.Methods and analysisA broad search of multiple electronic databases (Medline, Embase, Cochrane Central Register of Controlled Trials and Web of Science) will be conducted to identify studies published as of 13 November 2019, examining all-comers with cervical artery dissection observed over time. Studies will be screened by two independent reviewers in a two-level process to determine eligibility for inclusion. Data will be pooled from eligible articles and the main outcome of recurrent cervical artery dissection at 5 years will be determined using quantitative analysis.Ethics and disseminationEthics approval is not necessary as no primary data are being collected. The information will be disseminated in the form of a systematic review article which will be submitted to a peer-reviewed medical journal.Prospero registration numberCRD42020166105.
| S-EPMC7488837 | biostudies-literature