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Screening for Functional Non-coding Genetic Variants Using Electrophoretic Mobility Shift Assay EMSA and DNA-affinity Precipitation Assay DAPA
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The role of TPA I/D and PAI-1 4G/5G polymorphisms in multiple sclerosis

Maja Zivković1, Nada Starčević Čizmarević2, Luca Lovrečić3

  • 1Laboratory for Radiobiology and Molecular Genetics, "Vinča" Institute of Nuclear Sciences, University of Belgrade, 11000 Belgrade, Serbia.

Disease Markers
|May 15, 2014
PubMed
Abstract

Insights

Genetic variations in tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1) influence multiple sclerosis (MS) risk. The PAI-1 5G/5G genotype combined with the TPA I allele increases MS susceptibility, highlighting gene-gene interactions in this complex disease.

Area of Science:

  • Neuroimmunology
  • Genetics
  • Molecular Biology

Background:

  • Impaired fibrinolysis is observed in multiple sclerosis (MS).
  • Extracellular proteolytic enzymes are implicated in demyelinating neuroinflammatory disorders.
  • Tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1) are key regulators of fibrinolysis and proteolysis.

Purpose of the Study:

  • To investigate the association of TPA Alu I/D and PAI-1 4G/5G polymorphisms with MS susceptibility.
  • To analyze gene-gene interactions in MS pathogenesis.

Main Methods:

  • Genotyping of TPA Alu I/D and PAI-1 4G/5G polymorphisms using PCR-RFLP.
  • Study conducted within the Genomic Network for Multiple Sclerosis (GENoMS) cohort.
  • Analysis included 885 MS patients and 656 healthy controls from four Balkan populations.

Main Results:

  • TPA DD homozygosity demonstrated a protective effect against MS (OR=0.79, P=0.037).
  • PAI-1 5G5G genotype was identified as a risk factor for MS (OR=1.30, P=0.038).
  • A significant gene-gene interaction was observed, with the PAI-1 5G5G/TPA I allele combination increasing MS risk (OR=1.39, P=0.017).

Conclusions:

  • The combination of PAI-1 5G/5G genotype and TPA I allele significantly impacts MS susceptibility.
  • Gene-gene interactions play a crucial role in the complex etiology of multiple sclerosis.
  • These findings underscore the importance of studying genetic interactions in multifactorial diseases.

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