Investigation of genetic risk factors for cerebral small vessel disease and leukoaraiosis in Caucasian and African & Car

Lead Research Organisation: St George's University of London
Department Name: Cardiovascular Medicine

Abstract

Stroke is a major cause of death and disability, commonly caused by blood clots blocking large or small blood vessels of the brain. About one in five strokes are caused by disruption of blood flow in small vessels causing a lacunar stroke. This arises from diseased or hardened small blood vessels, known as small vessel disease (SVD). It can also cause widespread damage with loss of brain tissue structure, called leukoaraiosis. Lacunar stroke and leukoaraiosis is the most common cause of vascular dementia and a major cause of declining memory and thinking abilities that occurs with normal ageing.

SVD is particularly common in individuals of African and African-Caribbean ancestry. It is not known why some people acquire SVD or what exactly causes it. Evidence suggests that genetic or inherited factors are important in increasing risk. However, the culprit genes have not yet been identified.

New technology allows us to screen the whole of our genetic material to identify new genes causing diseases. We will examine brain scans and blood samples from stroke sufferers to try and identify genes associated with SVD in both White and Black stroke sufferers. Discovering new genes could lead to new treatments in this important disease.

Technical Summary

Stroke is a major cause of mortality and morbidity worldwide. 20% of ischaemic stroke is due to cerebral small vessel disease (SVD) which is also the leading cause of vascular dementia. Pathologically there is both focal microatheroma and diffuse arteriopathy affecting the perforating end-arteries. This causes lacunar infarcts and areas of incomplete ischaemic seen on MRI as white matter hyperintensity or leukoaraiosis. Leukoaraiosis also occurs in the absence of stroke and correlates with age-related cognitive decline. Despite its importance, however, there are few effective treatments for SVD and leukoaraiosis, and limited understanding of the pathogenesis. SVD is more than twice as common in British individuals of African ancestry.

There is compelling evidence for genetic risk factors in SVD and leukoaraiosis. As in other complex diseases, candidate gene studies have had little success in identifying the culprit genes. The advent of gene-chip technology has made it possible to screen up to 1 million variants across the human genome, not just candidate genes. Thus genome-wide association studies (GWAS) have discovered completely novel genes related to complex traits such as diabetes and leading to new therapeutic trials as in the case of macular degeneration. The first large scale GWAS in ischaemic stroke is underway in over 4000 cases as part of the WTCCC2 and led by the proposed host department.

This research is based on a genome-wide approach and aims to take advantage of this extraordinary resource of already genotyped cases to study genetic variants associated with clinical and radiological phenotypes in SVD. In 1000 well-phenotyped cases, leukoaraiosis lesion volume will be measured quantitatively on MRI. Leukoaraiosis will be used as a quantitative trait in a genome-wide association to identify associated single nucleotide polymorphisms. Positive associations will be replicated in a second Boston-based cohort of ischaemic stroke with MRI-measured leukoaraiosis. Following identification of significant variants the study will be extended to fine-mapping and haplotype analyses in order to identify causal variants. In a unique cohort of >1000 UK strokes in individuals of African and African Caribbean ancestry (SLESS), these variants will be examined to determine whether they are associated with the excess of SVD seen in this ethnic group.

The discovery of genetic variants associated with leukoaraiosis and SVD will lead to expression studies, pathway analysis and metabolomic studies which could identify novel disease mechanisms, biomarkers and therapies in cerebral SVD and maybe even small vessel disease in coronary heart disease.

Publications

10 25 50
 
Description Genome-wide Association Meta-analysis in Leukoaraiosis (Massachusetts General Hospital/Harvard and the Broad Institute) 
Organisation Center for Human Genetic Research; Broad Institute
Country United States 
Sector Academic/University 
PI Contribution At St George's we have analysed over 1500 MRI ischaemic stroke scans with genotype data for a genome-wide association study in Leukoaraiosis. Concurrently, the Boston team have analyzed 1200 scans. Genome-wide association studies require large numbers to be powered because of the corrections for multiple testing and small risk variant size effects. Currently a meta-analysis of the datasets is underway.
Impact Early results have been presented at the International Stroke Genetics Meeting in November 2011 in Jacksonville. However, there are as yet no publications. Both UK and US teams include clinical academics, bioinformaticians, geneticists and imaging scientists.
Start Year 2010
 
Description Visiting Fellowship 
Organisation Massachusetts General Hospital
Country United States 
Sector Hospitals 
PI Contribution Visiting fellowship to MGH (Boston) in October/November 2012 and worked with collaborators on new projects related to heritability of leukoaraiosis.
Collaborator Contribution Combined data from both centres for collaboration.
Impact paper entitled "The 17q25 locus is associated with white matter hyperintensity lesion volume in ischemic stroke patients, but not with lacunar stroke status" submitted to Stroke. Platform presentation at the American neurological Association October 2012.
Start Year 2008
 
Description American neurological Association 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact This study focused on 6 SNPs at the 17q25 locus that have previously been associated with cerebral white matter hyperintensities (WMH) on MRI. No significant difference in variation of these 6 SNPs was found in lacunar stroke compared to controls without stroke.

Presentation of research funded by the MRC
Year(s) Of Engagement Activity 2012