The role of TPA I/D and PAI-1 4G/5G polymorphisms in multiple sclerosis.
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.
Laboratory for Radiobiology and Molecular Genetics, "Vinča" Institute of Nuclear Sciences, University of Belgrade, 11000 Belgrade, Serbia.
Maja
M
Zivković
Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, 51000 Rijeka, Croatia.
Nada
N
Starčević Čizmarević
Clinical Institute of Medical Genetics, University Medical Centre, 1000 Ljubljana, Slovenia.
Luca
L
Lovrečić
Department of Neurology, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina.
Inge
I
Klupka-Sarić
Laboratory for Radiobiology and Molecular Genetics, "Vinča" Institute of Nuclear Sciences, University of Belgrade, 11000 Belgrade, Serbia.
Aleksandra
A
Stanković
Department of Neurology, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia.
Iva
I
Gašparović
Clinical Institute of Medical Genetics, University Medical Centre, 1000 Ljubljana, Slovenia.
Polona
0000-0002-8798-6575
P
Lavtar
Neurology Clinic, Military Medical Academy, 11000 Belgrade, Serbia.
Evica
E
Dinčić
Laboratory for Radiobiology and Molecular Genetics, "Vinča" Institute of Nuclear Sciences, University of Belgrade, 11000 Belgrade, Serbia.
Ljiljana
L
Stojković
Clinical Institute of Medical Genetics, University Medical Centre, 1000 Ljubljana, Slovenia.
Gorazd
G
Rudolf
Department of Neurology, University Medical Centre, 1000 Ljubljana, Slovenia.
Saša Sega
SS
Jazbec
Department of Neurology, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia.
Olivio
O
Perković
Department of Neurology, School of Medicine, University of Tuzla, 75000 Tuzla, Bosnia and Herzegovina.
Osman
O
Sinanović
Postgraduate Studies, School of Medicine, University of Rijeka, 51000 Rijeka, Croatia.
Juraj
J
Sepčić
Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, 51000 Rijeka, Croatia.
Miljenko
M
Kapović
Clinical Institute of Medical Genetics, University Medical Centre, 1000 Ljubljana, Slovenia.
Borut
B
Peterlin
Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, 51000 Rijeka, Croatia ; Department of Neurology, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia.
Smiljana
0000-0002-5484-6445
S
Ristić
D016022:Case-Control Studies; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D054643:INDEL Mutation; D009103:Multiple Sclerosis / Q000235:genetics*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011110:Polymorphism, Genetic; D012307:Risk Factors; D010959:Tissue Plasminogen Activator / Q000235:genetics*
D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D010959:Tissue Plasminogen Activator