RESUMO
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.
Assuntos
Isquemia Encefálica/genética , Ligação Genética , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético , Acidente Vascular Cerebral/genética , Idoso , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/metabolismo , Estudos de Casos e Controles , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Portugal , Fatores de Risco , Espanha , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/metabolismoRESUMO
OBJECTIVES: Replication of GWAS association findings remains the gold standard for results validation. Our aim was to test the association of four polymorphisms (rs1671021 in LLGL2, rs753307 in RUVBL2, rs6007897 and rs4044210 in CELSR1) previously identified as ischemic stroke (IS) risk factors in a phased GWAS performed on 6341 Japanese individuals [1]. METHODS: These polymorphisms were genotyped in a Portuguese sample of 566 IS cases and 525 controls, and their allele, genotype and haplotype associations were assessed. RESULTS: rs6007897 and rs4044210 in CELSR1 were associated with stroke risk individually (OR[95%CI]=1.43[1.13-1.81], p=0.003 and 1.38[1.09-1.74], p=0.007, respectively), and in combination as a haplotype. These associations remain after correction for multiple testing and in a meta-analysis with the original findings. The other polymorphisms were not associated. CONCLUSIONS: Our study independently confirmed for the first time the association between IS and CELSR1. This finding and the mechanisms by which these genetic variants exert their effects on stroke pathogenesis warrant further replication and investigation.
Assuntos
Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Caderinas/genética , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Adulto , Idoso , Alelos , Caderinas/fisiologia , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Portugal , Risco , Fatores de RiscoRESUMO
BACKGROUND: The association between methylenotetrahydrofolate reductase (MTHFR) 677TT and the increased risk of venous thrombosis is uncertain. Studies of this polymorphism in cerebral venous thrombosis (CVT) are inconclusive. OBJECTIVES: With a systematic review, we aimed to collect all case-control studies comparing the frequency of this polymorphism in CVT patients (cases) and healthy controls. METHODS: We used the MEDLINE, Cochrane Library and the ISI web of knowledge electronic databases and reference lists of retrieved articles in order to identify published case-control studies that evaluated the presence of MTHFR 677C>T polymorphism in CVT. Two reviewers independently selected studies. We compared the frequency of 677TT between cases and controls using the Mantel-Haenszel method, a fixed and a random-effects model in the pooled data. RESULTS: Nine case-control studies were included. The pooled analysis included 382 patients with CVT and 1217 controls. The frequency of 677TT genotype among CVT patients was not significantly higher compared with controls (15.7% versus 14.6%; OR=1.12, 95% confidence interval (95% CI) 0.80 to 1.58; p=0.50). There was significant heterogeneity between studies. CONCLUSIONS: This meta-analysis confirmed that there is currently insufficient data supporting that 677TT genotype is a risk factor for CVT. These results imply a continuing searching for the cause of CVT in patients with this polymorphism.