Epidemiology and genetics of stroke and its subtypes

Introduction

Stroke is the second commonest cause of death worldwide after coronary heart disease, and is a major cause of disability. The clinical burden and cost of stroke are at least as great as those due to heart disease or cancer, and are projected to increase rapidly as populations age. It affects mainly elderly people:

about half of all strokes occur in those over the age of 75.

Stroke (or 'brain attack') is a clinical syndrome, presenting with a rapid onset of focal (or at times global) dysfunction of the brain, caused by abrupt interruption of blood

supply to the brain because of a blocked or ruptured artery. There are three main pathological types. 80% of all strokes are ischaemic, while about 15% are due to intracerebral haemorrhage and 5% to subarachnoid haemorrhage. Each of these pathological types has various subtypes, whose underlying vascular pathology is

incompletely understood.

Our group is using a variety of epidemiological methods to attempt to:

• better understand the vascular pathologies underlying stroke subtypes (the stroke phenotype)
• establish which genes do (and do not) contribute to the risk of stroke, its subtypes, and various intermediate phenotypes.

Understanding stroke subtypes

We are particularly interested in how differences and similarities in risk factors and prognosis between lacunar (small vessel disease) stroke and other ischaemic stroke subtypes may inform us about the underlying vascular pathology. We are exploring these through a series of systematic reviews and meta-analyses, collaborative individual patient data analyses, and analyses of data from over 2500 patients in our hospital-based stroke register, the Edinburgh Stroke Study.

Stroke genetics:

About two thirds of stroke risk can be explained by variation in known risk factors: blood pressure, smoking, overweight, cholesterol, diet, physical inactivity, alcohol. While much of the risk of stroke is due to environmental influences ('nurture'), genetic factors ('nature') also have an important role. They may

directly affect known risk factors (e.g. by increasing blood pressure), modify known or unknown environmental influences (so-called 'gene-environment interaction'), or act through completely novel pathways. The genetic component of stroke is currently poorly understood, but many genes are probably involved, each exerting only a modest effect on the overall risk. Reliably identifying these genes is very important, since it may:

• increase our understanding of already known risk factors and how to influence them;
• identify previously unknown pathways that influence stroke risk;
• help us better to understand the differences between pathological types and subtypes of stroke.

We are using systematic review and meta-analysis methodology to assess the strength of the evidence for the contribution of various candidate genes to the risk of stroke, its subtypes and various intermediate phenotypes, including carotid intima-media thickness, leukoaraiosis and brain microbleeds.

Over the last few years we have collected DNA from around 1800 well-phenotyped patients in the Edinburgh Stroke Study (above), for genetic case-control and intermediate phenotype studies. We plan to perform these studies in collaboration with colleagues in the Edinburgh, and other groups in the UK and further afield.

Our work has been made possible through the support of the Wellcome Trust Clinical Research Facility, and funding from the Wellcome Trust, the Binks Trust, the Edinburgh Stroke Research Endowment Fund, and the School of Molecular and Clinical Medicine Strategic Research Fund.