Abstract
Introduction Multiple sclerosis is an inflammatory disease, where fibrin deposition and the impairment in its degradation have been shown to play an important role in the demyelination process. Tissue plasminogen activator (tPA) is a serine protease that enhances the conversion of plasminogen into its active form plasmin, the principal tPA inhibitor is the PAI-1. Several PAI-1 polymorphisms impact its gene expression and protein activity. Furthermore, the aim of this study was to investigate the association between the - 844 G>A, HindIII C>G, and 4G/5G PAI-1 polymorphisms and susceptibility to MS. Material and Methods The study group included 400 Mexican mestizo subjects: 200 unrelated patients and 200 unrelated individuals identified as control subjects. The analysis of PAI-1 polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism. Results A significant association was found between the CG genotype of the HindIII C>G PAI-1 polymorphism and susceptibility to MS (OR = 1.58, p = 0.03); moreover, the frequency of 5G allele and 5G/5G genotype of the 4G/5G PAI-1 polymorphism was statistically significant (OR = 1.36 and p = 0.04 and OR = 2.43 and p = 0.02, respectively). With respect to the relation between the scores of progression (EDSS) and severity (MSSS), no association was found between EDSS and genotypes of the PAI-1 polymorphisms analyzed. Regarding MSSS, male that carries genotype GA of the -844 G>A and genotype 4G/5G of the 4G/5G PAI-1 polymorphisms showed a significant association with an increase of media of MSSS in comparison with females (p = 0.01 in both cases).
Highlights
Multiple sclerosis is an inflammatory disease, where fibrin deposition and the impairment in its degradation have been shown to play an important role in the demyelination process
Altered plasminogen activator inhibitor 1 (PAI-1) levels observed in animal models have been associated with a diverse spectrum of diseases, low levels correlate with accelerated atherosclerosis and a defect in local angiogenesis; in counterpart, higher PAI-1 levels are found to be produced by malignant cells leading to a hypercoagulation state and in multiple sclerosis tissue interfering with fibrin degradation and contributing to axonal damage [5, 7]
94% were recurrent remittent multiple sclerosis (RRMS) and 6% were secondary progressive multiple sclerosis (SPMS). 51% of patients were treated with glatiramer acetate
Summary
Multiple sclerosis is an inflammatory disease, where fibrin deposition and the impairment in its degradation have been shown to play an important role in the demyelination process. It has been described that several PAI-1 polymorphisms impact in gene expression and protein activity; including the -675 4G/5G polymorphism where the individuals with the allele 4G present higher PAI-1 levels due to the lack of a binding site for a transcription repressor. HindIII polymorphism has been already studied in other disease such as systemic lupus erythematosus (SLE), recurrent miscarriages, and risk of ischemic stroke; but it has never been associated with multiple sclerosis [9, 10]. Based on this knowledge, the aim of this study was to investigate the association between the -844 G>A, HindIII C>G, and 4G/5G PAI-1 polymorphisms and susceptibility to MS in western Mexican population
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