Plazminojenaktivatör inhibitor-1(PAI-1) 4g/5g gen değişiminin uzun yaşama etkisi
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Date
2010
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Biyoteknoloji Enstitüsü
Abstract
Studies related to longevity genes gained a new perspective with the ?damage due to response? theory in recent years. The most important of these in the theory formation are metabolic events. According to the theory, accumulation of damage process formed response. Genes that ensure genetic control in these mechanisms are called ?longevity genes?. Thrombosis is a disease that has a multifactorial nature. Although it is thought that Factor V 1691 mutation has the leading effect for thrombosis, there are many other genetic effects play role together. Previous studies indicate that the increased plasminogen activator inhibitor-1 levels in thrombosis patients, fibrinolytic activity is decreased. The increased PAI-1 plasma level is related with the 4G/5G insertion/deletion polymorphism that found 675 upstream of the transkription start sequence in the promoter region. In this content, the aim of this study is to search the effect of PAI-1 675 4G/5G insertion/deletion alone and in combination with FVL on longevity.The healthy and patient subjects were divided into mainly two groups, i.e. 1 to 18 years and 70 and older. Each group was also divided into two as thrombotic and non-thrombotic. Peripheral venous blood samples were collected and phenol- chloroform method was used to extract DNA. Analysis of PAI?1 4G/5G polymorphism was carried out by PCR with the forward 5?CACAGAGAGAGTCTGGCCACGT3?and reverse 5?CCAACAGAGGACTCTTGGTCT3? primers. The amplified 98/99 bp PCR products were controlled by running them on 3% agarose gel. BseLI restriction endonuclease enzyme used to detect 4G/5G polymorphism. band profiles were seen in the 7% polyacrylamide gel electrophoresis to detect gene variations.For the PAI-1 4G/5G gene variation, when 70 and older patients compared to healthy group 4G allele heterozoygosity is found to have has a protective role(OR:0.45, p:0.003). Homozygosity for 4G allele seen as also a protective factor for 70 and older patients groups(OR:0.50, p:0.03). Moreover 5G allele homozygosity is a risk factor for the disease with 1.98 odds ratio and 0.03 p-value. PAI-1 4G/5G gene variation in combination with FVL mutation also have protective role for 70 and older in case of 4G heterozygosity and homozygosity(p:0.004 OR:0.44, p:0.03 OR:0.48).It is observed that increased plasma PAI-1 activity responsible for decreased fibrinolytic activity for the individuals that escape from angina pectoris, diabetes, myocardial infarction. 4G/5G polymorphism is related to transcriptional activation changes in the PAI-1 gene. PAI-1 gene 4G motif is determined to has more transcriptional activity than 5G motif and in correspondence with the experimental results 4G allele homozygosity cause increased PAI-1 protein levels and activity than 5G allele. Some studies suggested that 4G allele that relates with increased PAI-1 levels is a sign of increasing thrombotic risks. As PAI-1 4G/5G poymorphism is thought to play a role in pathogenesis of the mentioned fatal diseases, it is considered that the survival of individuals can be affected by this gene variation. In the previous thesis study was done in our department, FVL mutation shown to be a risk factor for thrombosis after birth and have effects on morbidity. Therefore, FVL mutation are expected to shorten the life span. However, examined our DNA samples showed although some individuals carry FVL mutation, they were identified as long-lived. The contribution of the study hypothesis that FVL and PAI-1 4G/5G has a relation and by this relation 0-18 and 70 and over individuals been included in the study, as a result it is determined that, 4G allele found to have a protective role for the eldery group whereas 5G allele is a risk factor for the disease.Key words: Thrombosis, PAI-1 4G/5G ins/del, FV1691 G-A, Longevity Genes
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Plazminojenaktivatör inhibitor-1, gen değişimi