Browsing by Author "Oliveira, S.A."
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- Association of a genetic variant in the ALOX5AP with higher risk of ischemic stroke: a case-control, meta-analysis and functional studyPublication . Domingues-Montanari, S.; Fernández-Cadenas, I.; Del Rio-Espinola, A.; Corbeto, N.; Krug, T.; Manso, H.; Gouveia, L.; Sobral, J.; Mendioroz, M.; Fernández-Morales, J.; Alvarez-Sabin, J.; Ribó, M.; Rubiera, M.; Obach, V.; Martí-Fàbregas, J.; Freijo, M.; Serena, J.; Ferro, J.M.; Vicente, A.M.; Oliveira, S.A.; Montaner, J.Variants in the 5-lipoxygenase-activating protein (ALOX5AP) and phosphodiesterase 4D (PDE4D) genes have first been associated with ischemic stroke (IS) through whole-genome linkage screens. However, association studies obtained conflicting results. We aimed to investigate the contribution of selected single nucleotide polymorphisms (SNPs) in these genes for the first time in a large Iberian population.
- Evidence for epistatic gene interactions between growth factor genes in stroke outcomePublication . Manso, H.; Krug, T.; Sobral, J.; Albergaria, I.; Gaspar, G.; Ferro, J.M.; Oliveira, S.A.; Vicente, A.M.Background and purpose: Growth factors are thought to modulate neurological function in stroke recovery through effects in angiogenesis, neurogenesis, and neuroprotection. Methods: We tested the association of variants in the brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA) genes, and epistatic interactions between them, with functional outcome in a sample of 546 stroke patients. Results: While none of the tested genes was independently associated with stroke outcome, two significant gene-gene interaction models were identified. One model combined one BDNF and three FGF2 markers, with a global odds ratio (OR) (95% confidence interval [CI]) of 4.15 [2.86-6.04]. The second model included one FGF2 and two VEGFA markers with a global OR [95% CI] = 2.54 [1.76-3.67]. Conclusions: The results provide evidence for gene interactions in stroke outcome, highlighting the complexity of the recovery mechanisms after a stroke event.
- Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studiesPublication . Traylor, M.; Farrall, M.; Holliday, E.G.; Sudlow, C.; Hopewell, J.C.; Cheng, Y.C.; Fornage, M.; Ikram, M.A.; Malik, R.; Bevan, S.; Thorsteinsdottir, U.; Nalls, M.A.; Longstreth, W.; Wiggins, K.L.; Yadav, S.; Parati, E.A.; Destefano, A.L.; Worrall, B.B.; Kittner, S.J.; Khan, M.S.; Reiner, A.P.; Helgadottir, A.; Achterberg, S.; Fernandez-Cadenas, I.; Abboud, S.; Schmidt, R.; Walters, M.; Chen, W.M.; Ringelstein, E.B.; O'Donnell, M.; Ho, W.K.; Pera, J.; Lemmens, R.; Norrving, B.; Higgins, P.; Benn, M.; Sale, M.; Kuhlenbäumer, G.; Doney, A.S.; Vicente, A.M.; Delavaran, H.; Algra, A.; Davies, G.; Oliveira, S.A.; Palmer, C.N.; Deary, I.; Schmidt, H.; Pandolfo, M.; Montaner, J.; Carty, C.; de Bakker, P.I.; Kostulas, K.; Ferro, J.M.; van Zuydam, N.R,; Valdimarsson, E.; Nordestgaard, B.G.; Lindgren, A.; Thijs, V.; Slowik, A.; Saleheen, D.; Paré, G.; Berger, K.; Thorleifsson, G.; Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2); Hofman, A.; Mosley, T.H.; Mitchell, B.D.; Furie, K.; Clarke, R.; Levi, C.; Seshadri, S.; Gschwendtner, A.; Boncoraglio, G.B.; Sharma, P.; Bis, J.C.; Gretarsdottir, S.; Psaty, B.M.; Rothwell, P.M.; Rosand, J.; Meschia, J.F.; Stefansson, K.; Dichgans, M.; Markus, H.S.; International Stroke Genetics Consortium.Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.
- A genome-wide association study using a DNA pooling strategy identifies BBS9 and GLIS3 as novel loci influencing patient’s outcome after strokePublication . Manso, H.; Paulos-Pinheiro, S.; Krug, T.; Sobral, J.; Albergaria, I.; Gaspar, G.; Ferro, J.M.; Oliveira, S.A.; Vicente, A.M.Stroke is a major cause of morbidity in developed countries and therefore finding adequate treatments to promote patient’s recovery is a priority task, requiring the elucidation of the molecular pathways influencing brain recovery. Few studies, however, have assessed the role of genes in stroke outcome. This study describes a pilot genome-wide association study (GWAS) to identify genetic factors contributing to patient’s outcome, using a DNA pooling design. Methods: Patient’s outcome was assessed using the modified Rankin Scale (mRS) three months after stroke. Using the 250K Affymetrix GeneChip Mapping Assay® – Nsp I, we compared SNP allele frequencies in a pool of non-disabled stroke patients (N=87, mRS=0), with a pool of severely disabled or deceased patients (N=100, mRS>=3). The 100 most interesting SNPs were selected for validation by individual genotyping. Results: 36 SNPs were validated, showing significant differences between patients with extremely good and extremely poor outcome at three months (1.7x10-4 ).
- Kalirin: a novel genetic risk factor for ischemic strokePublication . Krug, T.; Manso, H.; Gouveia, L.; Sobral, J.; Xavier, J.M.; Albergaria, I.; Gaspar, G.; Correia, M.; Viana-Baptista, M.; Simões, R.M.; Pinto, A.N.; Taipa, R.; Ferreira, C.; Fontes, J.R.; Silva, M.R.; Gabriel, J.P.; Matos, I.; Lopes, G.; Ferro, J.M.; Vicente, A.M.; Oliveira, S.A.Cerebrovascular and cardiovascular diseases are the leading causes of death and disability worldwide. They are complex disorders resulting from the interplay of genetic and environmental factors, and may share several susceptibility genes. Several recent studies have implicated variants of the Kalirin (KALRN) gene with susceptibility to cardiovascular and metabolic phenotypes, but no studies have yet been performed in stroke patients. KALRN is involved, among others, in the inhibition of inducible nitric oxide synthase, in the regulation of ischemic signal transduction, and in neuronal morphogenesis, plasticity, and stability. The goal of the present study was to determine whether SNPs in the KALRN region on 3q13, which includes the Ropporin gene (ROPN1), predispose to ischemic stroke (IS) in a cohort of Portuguese patients and controls. We genotyped 34 tagging SNPs in the KALRN and ROPN1 chromosomal region on 565 IS patients and 517 unrelated controls, and performed genotype imputation for 405 markers on chromosome 3. We tested the single-marker association of these SNPs with IS. One SNP (rs4499545) in the ROPN1-KALRN intergenic region and two SNPs in KALRN (rs17286604 and rs11712619) showed significant (P < 0.05) allelic and genotypic (unadjusted and adjusted for hypertension, diabetes, and ever smoking) association with IS risk. Thirty-two imputed SNPs also showed an association at P < 0.05, and actual genotyping of three of these polymorphisms (rs7620580, rs6438833, and rs11712039) validated their association. Furthermore, rs11712039 was associated with IS (0.001 < P < 0.01) in a recent well-powered genomewide association study (Ikram et al. 2009). These studies suggest that variants in the KALRN gene region constitute risk factors for stroke and that KALRN may represent a common risk factor for vascular diseases.
- Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaborationPublication . Malik, R.; Traylor, M.; Pulit, S.L.; Bevan, S.; Hopewell, J.C.; Holliday, E.G.; Zhao, W.; Abrantes, P.; Amouyel, P.; Attia, J.R.; Battey, T.W.; Berger, K.; Boncoraglio, G.B.; Chauhan, G.; Cheng, Y.C.; Chen, W.M.; Clarke, R.; Cotlarciuc, I.; Debette, S.; Falcone, G.J.; Ferro, J.M.; Gamble, D.M.; Ilinca, A.; Kittner, S.J.; Kourkoulis, C.E.; Lemmens, R.; Levi, C.R.; Lichtner, P.; Lindgren, A.; Liu, J.; Meschia, J.F.; Mitchell, B.D.; Oliveira, S.A.; Pera, J.; Reiner, A.P.; Rothwell, P.M.; Sharma, P.; Slowik, A.; Sudlow, C.L.; Tatlisumak, T.; Thijs, V.; Vicente, A.M.; Woo, D.; Seshadri, S.; Saleheen, D.; Rosand, J.; Markus, H.S.; Worrall, B.B.; Dichgans, M.; ISGC Analysis Group; METASTROKE collaboration; Wellcome Trust Case Control Consortium 2 (WTCCC2); NINDS Stroke Genetics Network (SiGN)Objective: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. Methods: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p , 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. Results: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency ,5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p , 1E-5). Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.
- Mitochondrial haplogroup H1 is protective for ischemic stroke in Portuguese patientsPublication . Rosa, A.; Fonseca, B.V.; Krug, T.; Manso, H.; Gouveia, L.; Albergaria, I.; Gaspar, G.; Correia, M.; Viana-Baptista, M.; Simões, R.M.; Pinto, A.N.; Taipa, R.; Ferreira, C.; Fontes, J.R.; Silva, M.R.; Gabriel, J.P.; Matos, I.; Lopes, G.; Ferro, J.M.; Vicente, A.M.; Oliveira, S.A.The genetic contribution to stroke is well established but it has proven difficult to identify the genes and the disease-associated alleles mediating this effect, possibly because only nuclear genes have been intensely investigated so far. Mitochondrial DNA (mtDNA) has been implicated in several disorders having stroke as one of its clinical manifestations. The aim of this case-control study was to assess the contribution of mtDNA polymorphisms and haplogroups to ischemic stroke risk.
- TTC7B emerges as a novel risk factor for ischemic stroke through the convergence of several genome-wide approachesPublication . Krug, T.; Gabriel, J.P.; Taipa, R.; Fonseca, B.V.; Domingues-Montanari, S.; Fernandez-Cadenas, I.; Manso, H.; Gouveia, L.O.; Sobral, J.; Albergaria, I.; Gaspar, G.; Jiménez-Conde, J.; Rabionet, R.; Ferro, J.M.; Montaner, J.; Vicente, A.M.; Silva, M.R.; Matos, I.; Lopes, G.; Oliveira, S.A.We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Several polymorphisms and haplotypes in the intron 5-intron 6 region of TTC7B were also associated with IS risk in the Spanish and combined data sets. Multiple independent lines of evidence therefore support the role of TTC7B in stroke susceptibility, but further work is warranted to identify the exact risk variant and its pathogenic potential.
- Variants of the Matrix Metalloproteinase-2 but not the Matrix Metalloproteinase-9 genes significantly influence functional outcome after strokePublication . Manso, H.; Krug, T.; Sobral, J.; Albergaria, I.; Gaspar, G.; Ferro, J.M.; Oliveira, S.A.; Vicente, A.M.Multiple lines of evidence suggest that genetic factors contribute to stroke recovery. The matrix metalloproteinases -2 (MMP-2) and -9 (MMP-9) are modulators of extracellular matrix components, with important regulatory functions in the Central Nervous System (CNS). Shortly after stroke, MMP-2 and MMP-9 have mainly damaging effects for brain tissue. However, MMPs also have a beneficial activity in angiogenesis and neurovascular remodelling during the delayed neuroinflammatory response phase, thus possibly contributing to stroke functional recovery.
- Variants within the nitric oxide synthase 1 gene are associated with stroke susceptibilityPublication . Manso, H.; Krug, T.; Sobral, J.; Albergaria, I.; Gaspar, G.; Ferro, J.M.; Oliveira, S.A.; Vicente, A.M.Animal studies have allowed important insights into the role of the nitric oxide synthase (NOS) enzymes in atherosclerosis and hypertension, as well as in stroke. In this study we tested the hypothesis that the NOS1 and NOS3 genes, respectively encoding neuronal NOS (nNOS) and endothelial NOS (eNOS), influence stroke susceptibility and outcome after a stroke event.