GRECOS Project (Genotyping Recurrence Risk of Stroke)

Abstract

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 models 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.

DNA Methylation in Stroke. Update of Latest Advances

“…In relation to stroke recurrence several studies in Asian populations [18] , [19] associations of ANRIL and NINJ2 polymorphisms with vascular recurrence. Other studies in Caucasian populations found associations between CRP and MGP polymorphisms and recurrent stroke [4] , [20] . However, other studies have not observed those associations [21] .…”

“…The risk of ischemic stroke recurrence after a first stroke is high, especially in the early stages, being around 6–12% within the first year of the initial stroke [4] . Moreover, stroke patients also have a high risk of developing other vascular diseases such as acute myocardial infarction and vascular death.…”

DNA methylation of MMPs and TIMPs in atherothrombosis process in carotid plaques and blood tissues

“…Methylation levels of MMPs and TIMPs in plaque tissue were crossed with methylation levels in blood tissue in two new independent cohorts. Ischemic strokecohort 1 (ISC-1): 37 atherothrombotic stroke patients and 6 healthy controls, from the GRECOS study [17]; Ischemic stroke-cohort 2 (ISC-2): 80 atherothrombotic patients from the BASICMAR prospective register [18] and 184 healthy controls from REGICOR population-based cohort (Supplementary Table 2). In both cases, only atherothrombotic stroke samples were selected as defined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) [19].…”

Matrix Gla protein polymorphism rs1800801 associates with recurrence of ischemic stroke

“…Moreover, no association was found with rs1800802 or rs4236. Fernández-Cadenas and colleagues recently reported that rs1800801 associated with first-year recurrent ischemic stroke in a Spanish cohort in the Genotyping Recurrence Risk of Stroke (GRECOS) study [9].…”

“…Achterberg and colleagues did not find an additional value of genetic information in predicting recurrence of vascular events including stroke after cerebral ischemia [8]. In the Genotyping Recurrence Risk of Stroke (GRECOS) project, however, Fernándes-Cadenas et al found an association of the single nucleotide polymorphism (SNP) rs1800801 in the matrix carboxyglutamatic acid Gla protein (MGP) gene with firstyear recurrent ischemic stroke in Spanish Caucasians [9]. MGP is an extracellular matrix protein involved in the inhibition of calcification of arteries and cartilage [10].…”