CADISPgenetics An ongoing Genetic Association Study on Cervical Artery Dissections

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CADISP-geneticsAn ongoing
Genetic
Association Study on Cervical Artery Dissections
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Epidemiology of cervical artery dissections
(CAD)

• CAD a major cause of ischemic stroke in young
  adults (mean age 44-46 years)
• Incidence in general population 2.6-2.9 /
  100,000 per year
• Suggested risk factors
• Neck trauma
• Recent infection
• Migraine
• Hyperhomocysteinemia
• Hypertension
• Fibromuscular dysplasia

Lee, Neurology 2006 Touzé, Neurology 2003
Rubinstein, Stroke 2005
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Arguments for a genetic predisposition to CAD

• CAD is associated with rare monogenic connective
  tissue disorders (e.g. vascular Ehlers-Danlos
  syndrome)
• In some large hospital-based cohorts familial
  cases of CAD up to 5 of CAD patients
• CAD patients more often present concomitant
  arterial anomalies
  
  
  
  
  fibromuscular dysplasia,
  aortic root dilation, intracranial aneurysms,
  arterial hyper-distensibility, endothelial
  dysfunction, temporal artery histological changes

Schievink, Stroke 1994 Schievink, Stroke 1996
de Bray, CVD 2007 Tzourio, Circulation 1997
Guillon, Neurology 2000 Lucas, CVD 2004
Schievink, J Neurosurg 1992 Volker, Neurology
2005
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Arguments for a genetic predisposition to CAD

• Half of CAD patients have connective tissue
  anomalies revealed by skin biopsy, with autosomal
  dominant inheritance pattern

Collagen fibers
Elastic fibers
Brandt , Ann Neurol1998 Brandt , Neurology,
2001 Wiest, Stroke 2006
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Previous genetic studies on CAD

• 9 studies screening candidate genes for
  mutations negative
• 4 linkage studies negative
• 15 genetic association studies
• ICAM1 (E469K) 1 positive study Longoni, 2006
• COL3A1 (3UTR 2bp deletion) 1 positive study Von
  Pein, 2002
• MTHFR (677TT)

1.67 (1.21, 2.31)
677TT deleterious
677TT protective
Debette Markus, Stroke in press
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Previous genetic studies on CAD

• The majority of genetic studies in CAD have been
  negative until now
• All previous genetic association studies were
  underpowered
• Sample size always
• Given low incidence, only a multicentre
  recruitment can reach a sufficient sample size

Debette Markus, Stroke in press
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The CADISP consortium

• CADISP Cervical Artery Dissections and Ischemic
  Stroke Patients
• Goals of the consortium
• Look for genetic variants associated with CAD
• Look for environmental risk factors of CAD
• Look for gene-environment interactions
• Therapeutic aspects addressed in setting of a
  multicenter registry
• www.cadisp.org
• http//clinicaltrials.gov/ct2/results?termCADISP

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CADISP centers
9 countries 20 neurological departments
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Study Design
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Patients with Ischemic stroke without CAD
Patients with Cervical
Artery Dissection
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Healthy controls
The 3 groups are matched on age (5-year
intervals), gender, geographical origin Only
individuals of European ethnicity are included
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Inclusion criteria
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Collected Data

• Standardized questionnaire
• Clinical, radiological, biological signs at acute
  phase
• Past medical history
• Family history
• Clinical signs of connective tissue disease
• Treatments
• Outcome at 3 months
• Biological data
• DNA
• Plasma
• Serum

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Analysis strategy

• Step 1 GWAS on CAD-group vs healthy controls
• Centre National de Génotypage, Evry (France)
  Dr. M Lathrop
• Illumina platform (probably 610K)
• Step 2 Replication of top hits in independent
  populations
• Step 3 Specificity analysis for confirmed
  associations (CAD-group vs. IS-group)

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Analysis strategy

• Step 1 GWAS on CAD-group vs healthy controls
• Centre National de Génotypage, Evry (France)
  Dr. M Lathrop
• Illumina platform (probably 610K)
• Step 2 Replication of top hits in independent
  populations
• Step 3 Specificity analysis for confirmed
  associations (CAD-group vs. IS-group)
• Complementary candidate gene association study
  (genes involved in connective tissue stability,
  endothelial function, and inflammatory pathways)

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Inclusions (Oct 2008)
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Timeline

• Number of inclusions by Oct 2008
• 1061 CAD-cases
• 743 IS-cases
• 2045 healthy controls available

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Timeline

• Number of inclusions by Oct 2008
• 1061 CAD-cases ? 1100 by Dec 2008
• 743 IS-cases ? 900 by Dec 2008 ? 1100 early 2009
• 2045 healthy controls available ? 2060 by Dec
  2008
• GWAS of CAD vs. healthy controls in Jan 2009

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Replication

• Please let us know if you have a DNA collection
  of CAD cases
• and if you would be interested in a
  collaboration!
• Contact stephanie.debette_at_pasteur-lille.fr

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CADISP investigators

• France
• Philippe Amouyel
• Jean Dallongeville
• Stéphanie Debette
• Maurice Giroud
• Olivier Godefroy
• Didier Leys
• Thierry Moulin
• Yves Samson
• Emmanuel Touzé
• Germany
• Tobias Brandt
• Martin Dichgans
• Armin Grau
• Caspar Grond-Ginsbach
• Manja Kloss
• Christoph Lichy

• Belgium
• Shérine Abboud
• Vincent Thijs
• Italy
• Simone Beretta
• Anna Bersano
• Valeria Caso
• Stefano Paolucci
• Alessandro Pezzini
• Maria Sessa
• Switzerland
• Stefan Engelter
• Philippe Lyrer
• UK
• Hugh Markus

• Finland
• Antti Metso
• Tiina Metso
• Turgut Tatlisumak
• Turkey
• Ayse Altintas
• Argentina
• Juan José Martin
• and many others

www.cadisp.org
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• THANK YOU!

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Power
Threshold if 5 independent candidate genetic
variants are tested Threshold if 50
independent candidate genetic variants are tested
Genome-wide significance (WTCCC, Nature 2007)