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31/03/2016 - Press release

Hospital del Mar and Vall d'Hebron take part in the biggest international genomic study into strokes

Researchers from the Hospital del Mar Medical Research Institute (IMIM), the Vall d'Hebron Research Institute (VHIR), and the MutuaTerrassa Foundation for Teaching and Research (FMT) have taken part in both phases of the study

The Hospital del Mar Medical Research Institute and the Vall d'Hebron Research Institute, in collaboration with the MútuaTerrassa Foundation, were the only Spanish research centres to participate in the largest study to date into genome association with ischaemic stroke, and which involved around 38,000 patients and 400,000 control subjects. The study, published recently in Lancet Neurology by two international consortia, has led to the identification of a gene implicated in atherothrombotic ischaemic stroke. The team of Dr. Jordi Jiménez-Conde, head of the Genetics Area within the Neurovascular Research Group at the IMIM and a neurologist at the Hospital del Mar, took part in the discovery phase of the study.

This first part involved the analysis of nearly 900 samples from stroke patients and 1200 controls from the Hospital del Mar, this being the second-ranked centre internationally according number of cases. Dr. Jiménez-Conde explains that "we analysed over 5 million genetic variants for each patient in order to determine, using a new clinical classification of ictus, which genes were associated with each subtype of ischaemic stroke."

Ischaemic strokes represent 85% of all strokes and occur when blood flow to the brain is interrupted by a blockage in an artery or blood vessel. According to the mechanism that produces the obstruction, five subtypes of ischaemic stroke have been established: atherothrombotic, affecting the major arteries; lacunar, taking place in smaller arteries; cardioembolic, caused by the obstruction of a vessel by a clot from the heart; uncertain, which either has more than one cause or an unknown origin; and 'other', which includes rare causes of stroke.

In this case, the researchers were able to detect genetic variants of a newly discovered gene, known as TSPAN2, associated with the risk of atherothrombotic stroke. This gene is expressed in blood vessels and blood, and up to this point had only been seen to have a genetic association with migraine.

To find this out, researchers from two consortia conducted a genome-wide association study in the first phase of the investigation, involving around 17,000 samples from stroke patients and 32,000 from healthy individuals. Once the association with this gene had been detected and confirmed together with others that had been described in previous studies, the researchers validated the results in a second phase involving 21,000 patients and 370,000 control cases.

Dr. Israel Fernández-Cadenas, head of the genetics area in the Neurovascular Diseases group at the VHIR and principal investigator in the Pharmacogenomics and Neurovascular Genetics lab of the MutuaTerrassa Foundation, took part in this second phase, along with Joan Montaner and Caty Carrera, also researchers at the VHIR . The scientists replicated the results using samples from 500 stroke patients from Vall d'Hebron University Hospital as well as 300 from healthy individuals.

"Our aim was to test whether the genes discovered in the first phase using the new ictus classification were also present in the stroke subtype of our sample patients", explains Dr. Fernández-Cadenas. For this reason, in the patient series we had to analyse over a thousand polymorphisms associated with certain subtypes of ischaemic stroke.

The next step for the researchers from the SiGN consortium and the International Stroke Genetics Consortium will not focus on this gene, but will repeat the study using a larger sample group. Dr. Fernández Cadenas states that "for other complex diseases, such as diabetes or heart attack, the large sample size we have used in this study would already have been enough to find a large number of genes associated with the disease; however, in the case of stroke, we have found that the study still has a low statistical power."

The next study is now about to begin and is expected to be carried out using a cohort that could include more than half a million individuals and in which about 9 million genetic variants could be analysed. Figures that Dr. Jiménez-Conde considers would have been unthinkable a few years ago: "With the development of technology and statistical tools for handling Big Data we are now able to manage databases that we previously could not deal with, and this will help us find new genes involved in the mechanisms that lead to different types of stroke", he comments.

Stroke is the second leading cause of death in developed countries and one of the main reasons for disability in adulthood. The known risk factors for the disease include high blood pressure, atrial fibrillation and diabetes mellitus. However, recent studies suggest that much of the risk could be attributed to inherited genetic variations. For this reason, work like this represents another step forwards in the search for potential biomarkers to predict the risk of disease and find therapeutic targets that prevent a fatal outcome.

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