Navegando por Palavras-chave "Polymorphism, Genetic"

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    Avaliação de polimorfismos de genes relacionados à hemostasia e de receptores de estrógeno como fatores de risco para desenvolvimento de trombose venosa cerebral
    (Universidade Federal de São Paulo (UNIFESP), 2011-02-21) Orikaza, Cristina Mary [UNIFESP]; Lourenco, Dayse Maria [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Cerebral venous thrombosis (CVT) is na uncommon disease with some particularities in relation to other-site thrombosis, including a higher frequency in young people, female sex and users of oral contraceptive (OC). Classic inherited risk factors for venous thromboembolism (VTE) and pulmonary embolism (PE) has already been investigated in CVT, yielding some controversial results. Objectives: to investigate in a case-control study the impact of polymorphisms of hemostasis and hormone genes on the risk of CVT in relation to other sites of VTE and of CVT in relation to controls. The polymorphisms included prothrombin mutation G20210A; Factor V Leiden; thrombin-activatable fibrinolysis inhibitor (TAFI) -1053 C/T, -438 G/A, -152 A/G, 505 G/A, 1040 C/T e 1542 C/T; plasminogen activator inhibitor-1 (PAI-1) 4G/5G; factor XIII Val34Leu and estrogen receptors (ER)-ƒÑ (-351A/G e -397 T/C) and ER-ƒÒ 1082 G/A. Patients and controls: the study population was composed of 72 CVT cases (56 women, median age 32.5, range 8-69 years), 128 VTE or PE cases (94 women, median age 38, range 17-70 years) and 143 normal controls (110 women, median age 37, range 18-66 years), sex, age and race matched. Methods: The polymorphisms were detected by PCR technique followed by enzyme digestion or allele-specific PCR. Results: when compared to controls, only prothrombin mutation increased the risk for CVT (OR 7.1; CI 95%: 1.77-28.3) and TEV (OR 5.48; CI 95%: 1.5-20.1). Among women, CVT risk related to prothrombin mutation was no longer significant after adjustment for hormone exposure (OR 0.13; CI 95% 0.02-0.97). Considering only men, the wild haplotype of ER-ƒÑ (351A e 397T) increased CVT risk in comparison to VTE (OR 5.53; CI 95% 1.08 - 28.19). However, due to the large confidence interval, it is necessary to confirm this finding with a higher number of male subjects. TAFI gene haplotypes demonstrated interesting differences in CVT group, with higher presence of cis effect. In cis effect, rare alleles segregate together in the same chromosome, which may cause cumulative effects in a single protein. In order to emphasize this result, it was demonstrated that the presence of wild haplotype TAFI 505G/1040C resulted in a protector effect of CVT compared to control (OR 0.54; CI 95%: 0.03-0.96) and VTE (OR 0.42; CI 95% 0.23-0.76) groups. Conclusions: Prothrombin mutation was a risk factor for CVT and VTE compared to controls. Hormonal exposure seems to modulate CVT risk determined by prothrombin mutation and PAI-1 4G4G. The haplotypes of ER-ƒÑ (351A and 397T) and of TAFI (505G and 1040C) were associated to CVT, increasing or lowering its risk, respectively. The other polymorphisms did not show any influence on CVT and VTE risk in this study population.
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    Estudo do polimorfismo genético da N-Acetiltransferase (NAT2) e a suscetibilidades ao câncer colorretal numa população brasileira da região de São Paulo
    (Universidade Federal de São Paulo (UNIFESP), 2010-04-28) Silva, Tiago Donizetti da [UNIFESP]; Forones, Nora Manoukian [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Backgrounds: Epidemiological and biological studies suggest that polymorphisms in activating enzymes may play a role in the susceptibility of cancer in particular with specific environmental exposures such as meat intake and cigarette smoking. Genetically determined differences in N-acetylation capacity by NAT2 (N acetyl transferase 2) has been important in the metabolism of HCA (heterocyclic amines) from cooked meats. The polymorphism of this gene result in fast (WT), intermediate (WT/Mx) or slow acetylators (Mx/Mx) phenotypes. Aim: We conducted a case-control study to investigate the possible effect of meat intake, cigarette smoking, genetic polymorphisms of NAT2 and colorectal cancer risk. Patients and Methods: Colorectal cancer patients were matched by sex and age with healthy controls individuals. Meat intake and cigarette smoking data were assessed by a questionnaire of food and cigarette frequency. We considered smokers, patients being active or previous smokers. DNA was extracted from peripheral blood and the genotypes of the polymorphism were assessed by PCR-restriction fragment length polymorphism (RFLP). Five NAT2 alleles were studied (WT, M1, M2, M3 and M4) using specific digestion enzymes Kpnl for M1, Taql for M2, BamHl for M3 and Mspl/Alul for M4. Results: 147 colorectal cancer patients, being 60% in the colon, 76 females and 212 controls were studied. The mean age of both groups was 62 years old. NAT2 slow acetylators (Mx/Mx) were observed in more than half of the individuals studied (59.8% in the case group and 51.9% in the control group). No significant differences were observed between the groups and the polymorphism of NAT2. The odds ratio for colorectal cancer in the slow acetylators was 1.38 (95 percent, interval confidence 0.90-2.12). Although the number of females was small (n=76 in the case group), we found a suggestion of a decreased risk of cancer in the intermediate acetylators individuals W/Mx (OR: 0.55; 0.29 – 1.02). This difference was not confirmed in males (OR: 0.56, 95 percent interval confidence 0.16-2.00). Between the NAT2 fast acetylators W/W or W/Mx, the intake of meat, more than 3 times a week, increased the risk of colorectal cancer (OR: 2.05; 95%IC: 1.01-4.16). No association between the meat intake and colorectal cancer risk was observed in NAT2 slow acetylators (OR: 1.38; 95%IC: 0.76-2.78). Conclusion: NAT2 slow acetylators genotypes were more common in cancer and controls. We did not find an association between colorectal cancer risk and polymorphism of NAT2. An increased risk of colorectal cancer had been detected in fast acetylators with an increased meat intake. Probably the high levels of HCA in meats in rapid acetylators increase the risk of colorectal cancer due to the constant exposure of the carcinogenic residues generated by the metabolites of this compound.
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    Splicing alternativo e polimorfismo gênico de moléculas do sistema imune
    (Universidade Federal de São Paulo (UNIFESP), 2006) Smirnova, Anna [UNIFESP]; Gerbase-Lima, Maria [UNIFESP]
    Muitos genes do genoma humano apresentam variações na sequência de DNA (polimorfismos) e também variações no splicing de mRNA (variantes de splicing, VS). A expressão de VS pode ser regulada dependendo do tipo e do estado de ativação celular, e também ser influenciada por polimorfismos. Os objetivos desta tese foram: (1) realizar busca de VS de 10 genes imunorregulatórios (TC/RG1, L TA, L TB, OX40, OX40L, BAFF, APR/L, BAFF-R, BCMA, e TACI) em células mononucleares do sangue periférico ativadas e não ativadas; (2) caracterizar polimorfismos de genes que se mostrassem interessantes em relação a VS; (3) estudar a expressão das VS dos genes selecionados em relação aos polimorfismos deste gene, ativação e tipo de linfócitos. Métodos: Novas VS foram identificadas por busca no banco de dados de ESTs e screening por RT-PCR (reverse-transcriptase polymerase chain reaction). A sua expressão foi quantificada por RT-PCR semi-quantitativo ou em tempo real. Os polimorfismos foram caracterizados utilizando enzimas de restrição e sequenciamento. Resultados: (1) identificamos sete novas VS do gene L TA, duas de BAFF e quatro de BCMA em células mononucleares de sangue periférico; todas elas podem codificar isoformas diferentes de proteína, a maioria truncadas; (2) verificamos que a expressão das VS do L TA é regulada diferencialmente em linfócitos ativados; (3) observamos que as VS do BAFF se expressam em baixos níveis em todos os tipos de células estudados e, as do BCMA, somente em células CD19+; (4) elaboramos uma nova estratégia para definição de haplótipos e provamos sua eficiência em relação aos haplótipos do gene L TA, em 102 indivíduos; (5) observamos expressão diferente de alelos do L TA em células de indivíduos heterozigotos, sem haver diferença na expressão entre indivíduos homozigotos. Conclusões: Apesar de haver dados abundantes no banco de ESTs, a busca experimental de novas VS é necessária. No exemplo do L TA, sugerimos que mesmo VS com ORF truncado e de baixa expressão podem ter importância funcional, pois são reguladas diferencialmente durante ativação de linfócitos. A nova estratégia de detecção de haplótipos, proposta neste estudo, é rápida e eficiente e pode ser aplicada para vários genes, principalmente para os quais em que a detecção, por RFLP, de pelo menos um polimorfismo já tenha sido padronizada. O estudo de expressão do LTA em relação aos polimorfismos indica a existência de um mecanismo de regulação de expressão dos alelos que atua somente quando os dois alelos estão presentes no mesmo indivíduo.