Role of Plasminogen Genetic Variants in Multiple Sclerosis Susceptibility

Multiple sclerosis (MS) is a chronic immune-mediated and neurodegenerative disease of the central nervous system characterized by complex genetic and environmental interactions. A recent investigation by Sadovnick et al. (2016) delves into the genetic underpinnings of MS, highlighting the potential role of plasminogen (PLG) genetic variants in disease susceptibility.

The study focuses on a rare missense variant in the plasminogen gene (PLG), specifically the p.G420D variant, which was identified in a multi-incident MS family. The researchers conducted a comprehensive analysis involving genotyping, exome sequencing, and segregation analysis to understand the impact of this variant on MS susceptibility.

Key Findings
Identification of p.G420D Variant:
The PLG p.G420D variant (rs139071351) was identified through exome sequencing in three members of a multi-incident MS family.
Segregation analysis in additional family members revealed that 26 out of 30 individuals diagnosed with MS carried the p.G420D variant. This included unaffected parents and non-diagnosed family members.

Penetrance and Linkage Analysis:
Despite reduced penetrance, linkage analysis supported the cosegregation of the PLG p.G420D variant with MS, with a maximum LOD score of 5.48.
Nonparametric linkage analysis resulted in a LOD score of 1.29.

Population-Based Association Study:
Genotyping the PLG p.G420D variant in 2160 MS patients and 886 controls from Canada identified 12 additional probands and one control with the variant.
The study expanded to include cohorts from Canada, France, Spain, Germany, Belgium, and Austria, involving a total of 14446 patients and 8797 controls.
Logistic regression analysis showed marginally significant associations in the Canadian and French cohorts but not in the combined European dataset (P = 0.117).

Rare Missense Variants:
Sequencing of PLG in 293 probands identified nine rare missense variants, three of which were observed exclusively in MS patients.
Although these variants were predicted to be damaging to protein function, segregation analysis did not support their pathogenicity.

Biological Plausibility
PLG is involved in various biological processes relevant to MS, including:
Immune Response: Plasmin, the active form of plasminogen, is crucial for the inflammatory response in the brain.
Blood-Brain Barrier (BBB) Permeability: Plasmin can alter BBB permeability by affecting astrocytes and endothelial cells.
Neuronal Viability: Plasmin affects neuronal plasticity and extracellular matrix-related neuronal death.
Myelin Degradation: Plasmin activates matrix metalloproteinases (MMPs), which play a key role in demyelination.

Conclusion
The investigation by Sadovnick et al. provides compelling evidence for the potential role of the PLG p.G420D variant in MS susceptibility. Despite the lack of a significant association in the combined European cohorts, the variant's involvement in critical pathways related to inflammation, BBB permeability, and myelin degradation underscores its biological relevance. Further genetic and functional studies are warranted to elucidate the precise role of PLG variants in MS pathogenesis.

References:
Sadovnick, A. D., Traboulsee, A. L., Bernales, C. Q., Ross, J. P., Forwell, A. L., Yee, I. M., ... & Vilariño-Güell, C. (2016). Analysis of plasminogen genetic variants in multiple sclerosis patients. G3: Genes, Genomes, Genetics, 6(7), 2073-2079.