GRECOS project (Genotyping Recurrence Risk of Stroke). The use of genetics to predict the vascular recurrence after stroke

Abstract

Altres ajuts: This study was funded by Marato TV3, by the Spanish stroke research network (INVICTUS-PLUS) and by Generacion project (PI15/01978) Instituto de Salud Carlos III. Dr Fernández-Cadenas is supported by the Miguel Servet program (CP12/03298), Instituto de Salud Carlos III. Several groups participate in the International Stroke Genetics Consortium and the Spanish Stroke Genetics Consortium. The Hospital del Mar is supported by Spain's Ministry of Health (III FEDER, RD12/0042/0020). Study recruitment and collection of data sets for the VISP trial were supported by a grant (R01 NS34447; PI James Toole) from the National Institute of Neurological Disorders and Stroke (NINDS). Genome-wide association studies genotyping (U01 HG004438l; PI David Valle), funded by the National Human Genome Research Institute and the Genomics and Randomized Trials (GARNET) Network (U01HG00516-03; co-PI Michèle M. Sale and Bradford B. Worrall), and genetic data cleaning was provided by the GARNET Coordinating Center (U01HG005157; PI Bruce S. Weir)

Background and Purpose-Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack (TIA). Clinical scores do not predict the whole vascular recurrence risk, therefore we aimed to find genetic variants associated with recurrence that might improve the clinical predictive mode is in IS. Methods-We analyzed 256 polymorphisms from 115 candidate genes in three patient cohorts comprising 4,482 IS or TIA patients. The discovery cohort was prospectively recruited and included 1,494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2,988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score), and generated risk groups using a classification tree method. Results-The analyses revealed that rs1800801 in the MGP gene (HR: 1.33, p= 9×10-03), a gene related to artery calcification, was associated with new IS during the first year of follow-up. This polymorphism was replicated in a Spanish cohort (n=1.305), however it was not significantly associated in a North American cohort (n=1.683). The GRECOS score predicted new IS (p=3.2×10-09) and could classify patients, from low risk of stroke recurrence (1.9%) to high risk (12.6%). Moreover, the addition of genetic risk factors to the GRECOS score improves the prediction compared to previous SPI-II score (p=0.03). Conclusions-The use of genetics could be useful to estimate vascular recurrence risk after IS. Genetic variability in the MGP gene was associated with vascular recurrence in the Spanish population.