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

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.

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.