Resumen de Estudios genéticos masivos en el ictus isquémico: factores de riesgo y pronóstico
Stroke is a complex disease that affects the brain and vascular system. This disease has a high mortality, being the second cause of death worldwide and the fist cause of disability in adults of developed countries. Currently, more than 30 loci have been found associated with ischemic stroke risk; however, these genetic risk factors did not explain all heritability associated with this disease. Additionally, little is known about the genetics behind stroke outcome. Recently, two Genome-Wide Association Studies had reported two new candidate genes for ischemic stroke outcome. However, even a large sample size has been used in these studies, the results found are fewer that the expected. This could be due to the high heterogeneity of ischemic stroke outcome.
The principal aims of this thesis were, on one hand, to explore whether new stroke genetic risk factors can be found in specific homogeneous populations, and, on the other hand, to find new genetic risk factors of ischemic stroke outcome by using a new approach focus on acute endophenotypes associated with stroke outcome. In order to reach the first aim, it has been performed a case-control genome-wide association analysis using a Spanish cohort as a discovery and an international cohort as replication, with an additional validation in a second independent Spanish cohort. For second aim, it has been studied the clinical variables associated with the acute phase outcome of ischemic stroke. The variable leukocyte count was selected as an interesting endophenotype to find new genetic risk factors associated with stroke outcome.
As a results of this research, a new locus associated with lacunar stroke risk has been described, giving new information about the physiopathology of this disease. Additionally, the enzyme codified in the candidate gen MAN2B1 is a potential biomarker for lacunar stroke diagnosis. Moreover, it has been described in this thesis the first locus associated with leukocyte counts during the acute phase of ischemic stroke that additionally was associated with stroke outcome. Thus, the genetic analysis of acute endophenotypes has been confirmed as a useful approach to find new genetic risk factors associated with stroke outcome.
