Student thesis: Doctoral thesis


    Stroke is a huge public health burden worldwide. It is the 3rd cause of death and 1st cause of disability, showing a negative impact not only on the quality of life of the affected patient but also on the family, with a large number of patients suffering functional dependence even more than one year after the event. Moreover, the cost for health care systems is severe because there are direct costs (e.g. hospital stay, rehabilitation, transportation, medical monitoring, pharmaceutical consumption), and indirect costs (e.g. loss of productivity of patients and caregivers, loss of activity, premature mortality). The object of this thesis was to explore stroke physiopathology from a genetic point of view. Indeed, there is an important genetic implication in stroke, discovered in the early nineties by twin and familiar aggregation studies, but the genes responsible for the inheritance remain largely undetermined.
    One of the first variants that was highlighted as a risk factor for ischemic stroke in an Icelandic population, was a haplotype located in the phosphodiesterase gene. Since then, a multitude of candidate-gene association studies have been released. However, from a practical point of view, there is still no solid evidence today to routinely determine any of those genes and to make stroke predictions among healthy or high risk people. One of the goals of this thesis was thus specifically to identify a panel of genetic factors that could be used as predictive markers for the disease and especially in the Spanish population. The strategy was to analyze some polymorphisms that were previously published for other populations (PDE4D and ALOX5AP genes) or for whom the association was still unclear although it has been extensively studied (ACE gene). We also included in our analysis a list of genes revealed from the first genome-wide association study in ischemic stroke and an extensive list of all the markers that we could identify more or less related to stroke from the literature. Our studies resulted in the identification of various genetic risk factors for ischemic stroke in the Spanish population, which could perhaps be used as markers in other populations as well. Namely, the markers identified are the rs10947803 of the KCNK17 gene, the rs7956957 of the LRP1 gene, the rs2276109 of the MMP12 gene, the rs5742912 of the SCNN1A gene, the rs10507391 of the ALOX5AP gene and the rs10275136 and rs310585 of the NOS3 gene. All the associations observed resisted adjustment for stroke clinical and demographic risk factors, correction for multiple testing by Bonferroni, except for the SNP in LRP1 and were replicated in an independent sample. Moreover, all SNPs except the one in LRP1 showed a clear influence on the function of the corresponding gene or protein.
    In summary, we identified 5 genetic risk variants for ischemic stroke in the LRP1, SCNN1A, MMP12 and NOS3 genes. This panel of polymorphisms improved risk discrimination from conventional clinical risk factors and permitted to classify subjects who could benefit from primary prevention. Moreover, four of those variants showed a clear association with functional analyses.
    Date of Award7 Oct 2010
    Original languageEnglish
    SupervisorJoan Montaner Villalonga (Director), Jose Alvarez Sabin (Director) & Israel Fernández Cadenas (Director)

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