RESUMO
Hypoxia-inducible factor-3α (HIF-3α), a member of HIF family, can mediate adaptive responses to low oxygen and ischemia. It is believed that HIF plays crucial roles in stroke-related diseases. However, there are no reports on the association between HIF-3α genetic variants and ischemic stroke (IS) susceptibility. Therefore, we examined the association between HIF-3α gene polymorphisms (rs3826795, rs2235095, and rs3764609) and IS risk. The study population included 302 controls and 310 patients with ischemic stroke. Three polymorphisms in HIF-3α (rs3826795, rs2235095, and rs3764609) were genotyped using SNPscan technique. Our study showed a strong association of rs3826795 in HIF-3α with the risk of IS. The genotype and allele frequencies were shown to differ between the two groups. The rs3826795 in an intron of HIF-3α was related to a prominent increased IS risk (AA vs GG adjusted odd ratio [OR], 2.21; 95% confidence intervals [95% CI], 1.10-4.44; P = 0.03; AA vs AG/GG OR = 1.74, 95% CI, 1.02-2.97, P = 0.04; A vs G OR = 1.48, 95% CI, 1.05-2.07, P = 0.02). Logistic regression analysis suggested that rs3826795 posed a risk factor for IS in addition to common factors. Furthermore, when compared to controls, increased levels of homocysteic acid and level of non-esterified fatty acid were found in the cases (P < 0.01). However, no significant association was found between rs2235095 or rs3264609 and IS risk. These findings indicated that the rs3826795 polymorphism may be a potential target for predicting the risk of IS.
Assuntos
Proteínas Reguladoras de Apoptose/genética , AVC Isquêmico/genética , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Idoso , Proteínas Reguladoras de Apoptose/metabolismo , Ácidos Graxos não Esterificados/sangue , Feminino , Frequência do Gene , Homocisteína/análogos & derivados , Homocisteína/sangue , Humanos , AVC Isquêmico/sangue , Masculino , Pessoa de Meia-Idade , Proteínas Repressoras/metabolismoRESUMO
INTRODUCTION: A previous work has discovered that chromosome 1q32 locus linked to the risk of systemic lupus erythematosus (SLE) and miR-181b located on the susceptibility site with downregulation inversely correlating to its target molecular interferon alpha 1 (IFNA1). The purpose of this study was to investigate the association of miR-181b and IFNA1 polymorphisms with IS risk. METHODS: The miR-181b rs322931, IFNA1 rs1332190, and rs10811543 were genotyped using a Multiplex SNaPshot assay. miR-181b expression levels in plasma of SLE patients and controls were analyzed using quantitative PCR. RESULTS: The rs322931 CT, CT/TT, and T allele exerted an increased trend of SLE risk (CT vs. CC: adjusted OR = 1.71, 95% CI 1.16-2.50, P = 0.01; CT/TT vs. CC: adjusted OR = 1.45, 95% CI 1.08-1.95, P = 0.01; T vs. C: adjusted OR = 1.38, 95% CI 1.07-1.79, P = 0.01). Combined genotypes of the rs322931 CT/TT+rs1332190 TT and the rs322931 CC+rs10811543 AG/AA also revealed an increased risk of SLE. Gene-gene interaction analysis showed that a three-locus model consisting of rs322931, rs1332190, and rs10811543 attributed an increased risk of SLE. Further genotype-phenotype analysis revealed that rs322931 CT/TT carriers displayed lower levels of miR-181b. CONCLUSIONS: These findings indicate that the miR-181b rs322931 may be singly and jointly responsible for the etiology of SLE by altering miR-181b expression.
Assuntos
Estudos de Associação Genética , Interferon-alfa , Lúpus Eritematoso Sistêmico , MicroRNAs , Modelos Genéticos , Herança Multifatorial , Polimorfismo Genético , Adolescente , Adulto , Feminino , Humanos , Interferon-alfa/sangue , Interferon-alfa/genética , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Masculino , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-IdadeRESUMO
Taurine-upregulated gene 1 (TUG1), a kind of long non-coding RNAs (lncRNAs), was up-regulated in ischaemic stroke (IS) with the function of promoting neuron apoptosis. In this study, we aimed to investigate the association of TUG1 polymorphisms with IS risk. The TUG1 polymorphisms were genotyped using a custom-by-design 48-Plex SNPscan kit. The promoter activity was measured using the dual luciferase reporter assay. Relative expression of TUG1 in IS patients was analysed using quantitative PCR and the binding of TUG1 rs2240183 polymorphism to transcription factor was analysed using chromatin immunoprecipitation (ChIP) assay. The rs2240183 CT/CC genotypes and C allele in the promoter of TUG1 were associated with an increased risk of IS (CT/CC vs. TT: adjusted OR = 1.70, 95% CI, 1.16-2.49, P = 0.006; C vs. T: adjusted OR = 1.47, 95% CI, 1.12-1.93, P = 0.005). Logistic regression analysis showed that the rs2240183 was a risk factor of IS besides TC, TG, HDL-C, LDL-C, VLDL-C, Apo-A1, Apo-B and NEFA. Further functional analysis revealed that the TUG1 rs2240183 C allele exhibited higher transcriptional activity and TUG1 expression levels (P < 0.01). The ChIP assay showed that the rs2240183 C allele binds to transcriptional factor GATA-1. These findings indicate that the rs2240183 C allele was associated with a higher risk of IS possibly by binding to GATA-1 and elevating TUG1 levels.
Assuntos
Isquemia Encefálica/genética , Fator de Transcrição GATA1/genética , Predisposição Genética para Doença , RNA Longo não Codificante/genética , Acidente Vascular Cerebral/genética , Alelos , Animais , Apoptose/genética , Isquemia Encefálica/patologia , Proliferação de Células/genética , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Acidente Vascular Cerebral/patologia , Ativação Transcricional/genéticaRESUMO
Genome-wide association study (GWAS) identified chromosome 12p13 rs12425791 and rs11833579 as susceptibility loci of ischemic stroke (IS) in a European population. However, conflicting results were obtained in subsequent replication analysis. miR-200c, located on chromosome 12p13, was found to have a neuroprotective effect on ischemia. Our aim of this study was to investigate the association of the rs12425791, rs11833579 and rs12904 in the binding site of miR-200c with the risk of IS. The rs12425791, rs11833579, and rs12904 were genotyped using a TaqMan allelic discrimination assay. The results were verified by Sanger sequencing. We found that the rs12904 AG/GG genotypes and G allele were associated with a decreased risk of IS (AG/GG vs. AA: adjusted OR = 0.64; 95% CI, 0.44-0.95; G vs. A: adjusted OR = 0.65; 95% CI, 0.46-0.93). The combined genotypes of the rs11833579AG/AA and rs12904AG/GG were also associated with a reduced risk of IS (OR = 0.65; 95% CI, 0.46-0.93). These findings suggest that the rs12904 may have a jointly protective effect against the risk of IS.