Browsing by Author "Sobral, J."
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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.
- 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.
- 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 in the inflammatory IL6 and MPO genes modulate stroke susceptibility through main effects and gene-gene interactionsPublication . Vicente, A.M.; Manso, H.; Krug, T.; Sobral, J.; Gaspar, G.; Oliveira, S.; Ferro, J.M.A complex interplay between genetic background, clinical and life-style factors and the environment is expected to ultimately regulate the onset, acute phase and outcome of stroke. There is substantial evidence that inflammation within the Central Nervous System contributes to stroke risk, and known clinical risk factors for stroke, like atherosclerosis, diabetes, obesity, hypertension, and peripheral infection, are associated with an elevated systemic inflammatory profile. The inflammatory response is equally of major importance in recovery and healing processes after stroke. In this study we tested the genetic association of major inflammatory players IL1B (2q14), IL6 (7p21), TNF (6p21.3) and MPO (17q23.1) with stroke susceptibility and with stroke outcome at three months, in a population sample of 672 patients and 530 controls, adjusting for demographic, clinical and life-style risk factors and/or stroke severity parameters. The apparent complexity of the inflammatory mechanisms in stroke, and the multiplicity of players involved suggest a concerted process, in which implicated molecules interact to tightly regulate each other. We therefore examined both independent gene effects and the occurrence of gene-gene interactions among the tested inflammatory genes in stroke risk and stroke recovery. Two IL6 and one MPO SNP were significantly associated with stroke risk after multiple testing correction (0.022 correctedP 0.042), highlighting gene variants of low to moderate effect in stroke risk. An epistatic interaction between the IL6 and MPO genes was also identified in association with stroke susceptibility (P=0.031 after 1000 permutations). In the subset of 546 patients assessed for stroke outcome at three months using the modified Rankin Scale (mRS), we found one IL6 haplotype associated with stroke outcome (correctedP=0.024). In the present study we present supporting evidence for a role of the IL6 and MPO inflammatory genes in stroke susceptibility, and show that stroke risk is modulated by main gene effects together with clinical and life-style factors as well as by gene-gene interactions. Our findings are compatible and strengthen previous genetic and biological observations, highlighting the need of further functional studies, particularly in view of the possible utility of IL-6 as a diagnostic and/or prognostic biomarker for stroke.
- 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.