Dataset Information

Genetic Imbalance in Patients with Cervical Artery Dissection.

ABSTRACT:

Background

Genetic 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).

Conclusion

The 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.

SUBMITTER: Grond-Ginsbach C

PROVIDER: S-EPMC5345335 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Publications

Genetic Imbalance in Patients with Cervical Artery Dissection.

Grond-Ginsbach Caspar C Chen Bowang B Krawczak Michael M Pjontek Rastislav R Ginsbach Philip P Jiang Yanxiang Y Abboud Shérine S Arnold Marie-Luise ML Bersano Anna A Brandt Tobias T Caso Valeria V Debette Stéphanie S Dichgans Martin M Geschwendtner Andreas A Giacalone Giacomo G Martin Juan-José JJ Metso Antti J AJ Metso Tiina M TM Grau Armin J AJ Kloss Manja M Lichy Christoph C Pezzini Alessandro A Traenka Christopher C Schreiber Stefan S Thijs Vincent V Touzé Emmanuel E Del Zotto Elisabetta E Tatlisumak Turgut T Leys Didier D Lyrer Philippe A PA Engelter Stefan T ST

Current genomics 20170401 2

<h4>Background</h4>Genetic 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 ...[more]

PMID: 28367076

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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.

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.

Dataset Information

Genetic Imbalance in Patients with Cervical Artery Dissection.

Background

Conclusion

Publications

Genetic Imbalance in Patients with Cervical Artery Dissection.

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