The Role of TPA I/D and PAI-1 4G/5G Polymorphisms in Multiple Sclerosis

Abstract

Background. Previous studies have shown impaired fibrinolysis in multiple sclerosis (MS) and implicated extracellular proteolytic enzymes as important factors in demyelinating neuroinflammatory disorders. Tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1) are key molecules in both fibrinolysis and extracellular proteolysis. In the present study, an association of the TPA Alu I/D and PAI-1 4G/5G polymorphisms with MS was analyzed within the Genomic Network for Multiple Sclerosis (GENoMS). Methods. The GENoMS includes four populations (Croatian, Slovenian, Serbian, and Bosnian and Herzegovinian) sharing the same geographic location and a similar ethnic background. A total of 885 patients and 656 ethnically matched healthy blood donors with no history of MS in their families were genotyped using PCR-RFLP. Results. TPA DD homozygosity was protective (OR = 0.79, 95% CI 0.63–0.99, P = 0.037) and PAI 5G5G was a risk factor for MS (OR = 1.30, 95% CI 1.01–1.66, P = 0.038). A significant effect of the genotype/carrier combination was detected in 5G5G/I carriers (OR = 1.39 95% CI 1.06–1.82, P = 0.017). Conclusions. We found a significantly harmful effect of the combination of the PAI-1 5G/5G genotype and TPA I allele on MS susceptibility, which indicates the importance of gene-gene interactions in complex diseases such as MS.

Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex

“…4 Together with our own observations, these findings suggest that BBB disruption may be a feature of MS cortical pathology in the progressive phase. 18 Interestingly, PAI-1 is also upregulated in CSF and blood serum of MS patients, and polymorphisms of the PAI-1 gene have recently been linked to disease risk, providing further support to suboptimal clearance of coagulation proteins in MS. 16,17,19 Our finding of significant upregulation of PAI-1 in progressive MS cases in which fibrin(ogen) deposition is most severe implies that dysregulation of PAI-1 might impair the clearance of fibrin(ogen) and allow its pathological accumulation in late-stage MS. Other possible sources of fibrin(ogen) include synthesis by resident neurons and glia and/or retrograde transport in damaged axons in WM areas exposed to accumulated serum proteins. 5 This may be explained by the fact that most large serum proteins do not get converted to an insoluble matrix like fibrinogen does to fibrin, precluding accurate assessment in progressive MS.…”

“…Several lines of evidence suggest that the coagulation pathway is perturbed in MS. Proteomic assessment of active plaques has shown specific dysregulation of coagulation proteins, 15 and PAI-1 is upregulated in white matter lesions, where it has been associated with a failure of fibrinolysis. 18 Interestingly, PAI-1 is also upregulated in CSF and blood serum of MS patients, and polymorphisms of the PAI-1 gene have recently been linked to disease risk, providing further support to suboptimal clearance of coagulation proteins in MS. 16,17,19 Our finding of significant upregulation of PAI-1 in progressive MS cases in which fibrin(ogen) deposition is most severe implies that dysregulation of PAI-1 might impair the clearance of fibrin(ogen) and allow its pathological accumulation in late-stage MS. Other possible sources of fibrin(ogen) include synthesis by resident neurons and glia and/or retrograde transport in damaged axons in WM areas exposed to accumulated serum proteins. 25 Experimental evidence for these alternative cellular sources of fibrin(ogen) is lacking.…”

“…It is not currently possible to distinguish between fibrin and fibrinogen in postmortem specimens, largely because of their molecular similarity and shared epitopes, and hence the commonly used term fibrin(ogen). 19 These observations provide a compelling rationale to revisit cortical fibrin(ogen) deposition and PAI-1 expression and their relationships to neuronal damage in MS postmortem tissue. 6,7 Animal models of MS have implicated fibrin(ogen) deposition and PAI-1 dysregulation in disease pathogenesis.…”

“…[16][17][18] The potential clinical relevance of elevated PAI-1 is highlighted by the recent observation that PAI-1 polymorphisms are linked to MS susceptibility. 19 These observations provide a compelling rationale to revisit cortical fibrin(ogen) deposition and PAI-1 expression and their relationships to neuronal damage in MS postmortem tissue. Assessment of fibrin(ogen) deposition at late stages of MS, wherein cortical parenchymal inflammation is sparse, has not been undertaken to date.…”

Hemostasis biomarkers in multiple sclerosis

“…Plasminogen activator inhibitor 1 levels have been reported to be higher in MS patients during exacerbations and genetic polymorphisms of PAI‐1, linked to lower PAI‐1 plasma levels, are associated with increased risk of developing MS .…”