Towards the genetic basis of cerebral venous thrombosis—the BEAST Consortium: a study protocol

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Abstract

Introduction

Cerebral venous thrombosis (CVT) is a rare cerebrovascular condition accounting for <1% of all stroke cases and mainly affects young adults. Its genetic aetiology is not clearly elucidated.

Methods and analysis

To better understand the genetic basis of CVT, we have established an international biobank of CVT cases, Biorepository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) which aims to recruit highly phenotyped cases initially of European descent and later from other populations. To date we have recruited 745 CVT cases from 12 research centres. As an initial step, the consortium plans to undertake a genome-wide association analysis of CVT using the Illumina Infinium HumanCoreExome BeadChip to assess the association and impact of common and low-frequency genetic variants on CVT risk by using a case–control study design. Replication will be performed to confirm putative findings. Furthermore, we aim to identify interactions of genetic variants with several environmental and comorbidity factors which will likely contribute to improve the understanding of the biological mechanisms underlying this complex disease.

Ethics and dissemination

BEAST meets all ethical standards set by local institutional review boards for each of the participating sites. The research outcomes will be published in international peer-reviewed open-access journals with high impact and visibility. The results will be presented at national and international meetings to highlight the contributions into improving the understanding of the mechanisms underlying this uncommon but important disease. This international DNA repository will become an important resource for investigators in the field of haematological and vascular disorders.

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Most cited references 33

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Genome-wide association studies for complex traits: consensus, uncertainty and challenges.

Mark McCarthy, Gonçalo R Abecasis, Lon Cardon … (2008)

The past year has witnessed substantial advances in understanding the genetic basis of many common phenotypes of biomedical importance. These advances have been the result of systematic, well-powered, genome-wide surveys exploring the relationships between common sequence variation and disease predisposition. This approach has revealed over 50 disease-susceptibility loci and has provided insights into the allelic architecture of multifactorial traits. At the same time, much has been learned about the successful prosecution of association studies on such a scale. This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management.

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Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT).

José M. Ferro, Patrícia Canhão, Jan Stam … (2004)

The natural history and long-term prognosis of cerebral vein and dural sinus thrombosis (CVT) have not been examined previously by adequately powered prospective studies. We performed a multinational (21 countries), multicenter (89 centers), prospective observational study. Patients were followed up at 6 months and yearly thereafter. Primary outcome was death or dependence as assessed by modified Rankin Scale (mRS) score >2 at the end of follow-up. From May 1998 to May 2001, 624 adult patients with CVT were registered. At the end of follow-up (median 16 months), 356 patients (57.1%) had no symptom or signs (mRS=0), 137 (22%) had minor residual symptoms (mRS=1), and 47 (7.5%) had mild impairments (mRS=2). Eighteen (2.9%) were moderately impaired (mRS=3), 14 (2.2%) were severely handicapped (mRS=4 or 5), and 52 (8.3%) had died. Multivariate predictors of death or dependence were age >37 years (hazard ratio [HR]=2.0), male sex (HR=1.6), coma (HR=2.7), mental status disorder (HR=2.0), hemorrhage on admission CT scan (HR=1.9), thrombosis of the deep cerebral venous system (HR=2.9), central nervous system infection (HR=3.3), and cancer (HR=2.9). Fourteen patients (2.2%) had a recurrent sinus thrombosis, 27 (4.3%) had other thrombotic events, and 66 (10.6%) had seizures. The prognosis of CVT is better than reported previously. A subgroup (13%) of clinically identifiable CVT patients is at increased risk of bad outcome. These high-risk patients may benefit from more aggressive therapeutic interventions, to be studied in randomized clinical trials.

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Thrombosis of the cerebral veins and sinuses.

Jan Stam (2005)

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Author and article information

Journal

Journal ID (nlm-ta): BMJ Open

Journal ID (iso-abbrev): BMJ Open

Journal ID (hwp): bmjopen

Journal ID (publisher-id): bmjopen

Title: BMJ Open

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2044-6055

Publication date Collection: 2016

Publication date (Electronic): 22 November 2016

Volume: 6

Issue: 11

Electronic Location Identifier: e012351

Affiliations

[1 ]Institute of Cardiovascular Research Royal Holloway, University of London (ICR2UL) , London, UK

[2 ]Department of Gastroenterology and Hepatology, University of Oxford, Oxford University Hospitals NHS Trust , Oxford, Oxfordshire, UK

[3 ]Department of Restorative Neuroscience, Imperial College London , London, UK

[4 ]Department of Neurology, Helsinki University Central Hospital , Helsinki, Finland

[5 ]Department of Neurology, Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands

[6 ]Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico , Milan, Italy

[7 ]Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia , Brescia, Italy

[8 ]Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia , Brescia, Italy

[9 ]Department of Neurosciences, Hospital de Santa Maria, University of Lisbon , Lisbon, Portugal

[10 ]Department of Neurology, University of Utah , Salt Lake City, Utah, USA

[11 ]Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia , Foggia, Italy

[12 ]Atherosclerosis and Thrombosis Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo , Foggia, Italy

[13 ]Department of Neurology, University of Athens School of Medicine, Eginition Hospital , Athens, Greece

[14 ]Stroke Clinic, National Institute of Neurology and Neurosurgery Manuel Velasco Suarez , Mexico City, Mexico

[15 ]Department of Pathology and Molecular Medicine, Population Health Research Institute and Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences, McMaster University , Hamilton, Ontario, Canada

[16 ]Department of Neurology, Bordeaux University Hospital, Bordeaux University , Bordeaux, France

[17 ]Neurology Unit, Stroke Unit, Arcispedale Santa Maria Nuova—IRCCS , Reggio Emilia, Italy

[18 ]Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, University of Melbourne , Heidelberg, Victoria, Australia

[19 ]Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg , Gothenburg, Sweden

[20 ]Department of Neurology, Sahlgrenska University Hospital , Gothenburg, Sweden

Author notes

[Correspondence to ] Dr Ioana Cotlarciuc; ioana.cotlarciuc@ 123456rhul.ac.uk

IC and TM contributed equally to this work

Article

Publisher ID: bmjopen-2016-012351

DOI: 10.1136/bmjopen-2016-012351

PMC ID: 5128947

PubMed ID: 27881526

SO-VID: 6106d33f-ea1a-40cd-a443-eef2fcfc3492

Copyright © Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

License:

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

History

Date received : 19 April 2016

Date revision received : 13 October 2016

Date accepted : 3 November 2016

Funding

Funded by: Stroke Association, http://dx.doi.org/10.13039/501100000364;

Award ID: TSA 2016/01

Funded by: Dowager Countess Eleanor Peel Trust, http://dx.doi.org/10.13039/501100000832;

Award ID: MBE/12005960.1

Towards the genetic basis of cerebral venous thrombosis—the BEAST Consortium: a study protocol

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Abstract

Introduction

Methods and analysis

Ethics and dissemination

Related collections

Probing cerebral hemodynamics with BOLD fMRI

Most cited references 33

Genome-wide association studies for complex traits: consensus, uncertainty and challenges.

Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT).

Thrombosis of the cerebral veins and sinuses.

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