Percorrer por autor "Ferro, J.M."
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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.
- The role of ADH1B in alcohol consumption and stroke susceptibilityPublication . Paulos-Pinheiro, S.; Coelho, J.I.; Albergaria, I.; Gaspar, G.; Ferro, J.M.; Vicente, A.M.While heavy episodic drinking has been shown to be harmful to the heart, moderate alcohol consumption is thought to be protective against cardiovascular disease, through the regulation of rising HDL cholesterol levels. The cardio-protective effect of alcohol is now not thought to vary by beverage type. In fact, evidence for an additional cardio-protective effect of antioxidant polyphenols in red wine is weak. The study of genetics variants of the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes involved in alcohol metabolism is important to understand the patterns of drinking habits and its effects in stroke susceptibility. The enzyme alcohol dehydrogenase (ADH), which oxidizes alcohol to acetaldehyde, has proven to play an important role in alcohol metabolism. Seven genes encoding ADH are found in a tight cluster on chromosome 4 and some are polymorphic in white European populations. More active variants of ADH cause higher concentrations of acetaldehyde in the body following alcohol consumption and are therefore protective against drinking. Functional variants in both ADH1B and ADH1C have been associated with alcohol consumption or alcohol dependence. The ADH1B variant (rs1229984) has emerged as the most strongly associated with alcohol phenotypes and is therefore the most suitable instrument for Mendelian randomization studies in Europeans. The A allele has an allele frequency of approximately 2-5% in Europeans and plays a protective role against heavy drinking because it confers an higher alcohol metabolic rate and consequent accumulation of toxic acetaldehyde.
- 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.