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Genetics of Multifactorial Stroke

The Genetics of Complex Multifactorial Stroke has recently become another research focus of the group. Ischemic Stroke (IS) is a heterogenous condition. Epidemiologic data provide substantial evidence for a genetic component to complex multifactorial stroke, but the extent of predisposition remains unknown. Most likely there are many alleles with small effect sizes.

Projects

  • Candidate Gene Association Studies on Hemorrhagic and Ischemic Stroke including stroke subtypes (Small vessel disease, Large Artery Disease, Cardiac Disease, etc.). There is a close collaboration with the group of Prof. H. Markus (London)
  • We are aiming for a Genome-Wide Association study in IS in collobaration with other groups

Background

Candidate gene association studies on a wide range of candidate pathways such as the haemostatic and inflammatory system, homocysteine metabolism, and the renin-angiotensin aldosterone system suggest a weak but significant influence for several at risk alleles. Genome-wide linkage studies in extended pedigrees from Iceland have led to the identification of the PDE4D and ALOX5AP gene. Specific haplotypes in these genes have been shown to confer risk to IS in the Icelandic population but their role in other populations remains to be determined. Advances in high throughput genotyping and biostatistics have enabled new study designs including genome-wide association studies. Their application to IS requires the collaborative efforts of multiple centres. This will contribute to the identification of additional genes, novel pathways and eventually novel therapeutic approaches to ischemic stroke.

References

Lõhmussaar E, Gschwendtner A, Mueller J, Org T, Wichmann E, Hamann G, Meitinger T, Dichgans M. The ALOX5AP gene and the PDE4D gene in a Central-European population of stroke patients Stroke 2005;36:731-763 Pubmed

Dichgans M. The Genetics of Ischemic Stroke. Lancet Neurology  2007;6:149-161
 
Dichgans M, Hegele RA. Update on the Genetics of Stroke and Cerebrovascular Disease. Stroke  2007;38:216-218

Dichgans M, Hegele RA. Update on the genetics of stroke and cerebrovascular
disease 2008. Stroke. 2009 May;40(5):e289-91.

Freilinger T, Bevan S, Ripke S, Gschwendtner A, Lichtner P, Müller-Myhsok B, Wichmann HE, Markus HS, Meitinger T, Dichgans M. Genetic variation in the lymphotoxin-alpha pathway and the risk of ischemic stroke in European populations. Stroke. 2009 Mar;40(3):970-2

Gschwendtner A, Bevan S, Cole JW, Plourde A, Matarin M, Ross-Adams H, Meitinger T, Wichmann E, Mitchell BD, Furie K, Slowik A, Rich SS, Syme PD, MacLeod MJ, Meschia JF, Rosand J, Kittner SJ, Markus HS, Müller-Myhsok B, Dichgans M; International Stroke Genetics Consortium. Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. Ann Neurol. 2009 May;65(5):531-9

Collaborations

  • Prof. Hugh Markus (London)
  • Prof. Thomas Meitinger (GSF, Neuherberg, München)

Links