Exome Sequencing Study Identifies Key Variants in Multiple Sclerosis Disease Course
Multiple sclerosis (MS) is a complex neurological disorder where both genetic and environmental factors contribute to its onset and progression. While extensive studies have uncovered genetic variants influencing MS susceptibility, understanding the genetic factors that determine the disease course—whether a patient experiences a benign or aggressive form of MS—remains a challenge. A recent study by Gil-Varea et al. sheds light on this issue by using exome sequencing to identify genetic variants associated with different disease phenotypes in MS patients.
Background and Objective
The study aimed to identify genetic polymorphisms that modulate the course of MS by focusing on benign and aggressive disease phenotypes. The researchers conducted exome sequencing on 20 MS patients—10 with benign disease and 10 with aggressive disease. This discovery cohort allowed them to explore variants potentially associated with disease severity. To ensure the reliability of their findings, the team further validated these variants in two independent cohorts of MS patients.
Methods
MS patients were classified based on clinical criteria: benign cases had a disability score (EDSS) ≤ 3 after 15 years without treatment, while aggressive cases reached an EDSS ≥ 6 within 5 years. After performing exome sequencing and comparing allele frequencies, the researchers identified 16 single nucleotide polymorphisms (SNPs) as potential candidates for validation.
The first validation cohort consisted of 194 MS patients, while the second cohort included 257 patients, each classified as having benign or aggressive MS. Statistical analyses, including meta-analyses, were performed to validate the significance of these SNPs.
Key Findings
The study uncovered three SNPs in particular—rs28469012, rs10894768, and rs10423927—that were associated with MS disease course. These SNPs were located in the CPXM2, IGSF9B, and NLRP9 genes, respectively, and each gene showed potential involvement in immune system regulation and neuroinflammation.
CPXM2 (Carboxypeptidase X, M14 family, member 2):
SNP rs28469012 was significantly associated with an aggressive MS phenotype. CPXM2 belongs to a family of proteins involved in synaptic integrity, and its role in neurodegeneration, such as in Alzheimer's and Parkinson’s disease, has been previously suggested. This finding provides a new angle for exploring its influence in MS, particularly in the context of neuroinflammation and disease progression.
IGSF9B (Immunoglobulin Superfamily Member 9B):
SNP rs10894768 was more frequent in patients with a benign disease course. IGSF9B plays a role in maintaining inhibitory synapses in the brain, and the researchers hypothesized that its variants might help mitigate the severity of MS by preserving synaptic function. The expression of IGSF9B in astrocytes and microglia, cells involved in neuroinflammation, reinforces its potential role in modulating disease outcomes.
NLRP9 (NLR Family Pyrin Domain Containing 9):
SNP rs10423927 showed a trend toward association with benign MS. NLRP9 is part of the NOD-like receptor (NLR) family, which is critical in immune system function and inflammation. Though less studied in MS, its involvement in regulating immune responses through inflammasome activation presents an interesting target for further research.
Brain Tissue Analysis and Functional Implications
To explore the potential effects of these genetic variants at the cellular level, the study included brain tissue analysis from MS patients. Immunohistochemistry revealed that IGSF9B, CPXM2, and NLRP9 were primarily expressed in astrocytes and microglia, cells crucial to the central nervous system's inflammatory response. This expression was notably prominent in chronic active lesions, suggesting that these genes might influence the local inflammatory environment in MS.
The researchers also analyzed gene expression in peripheral blood mononuclear cells (PBMCs) but found no significant differences between carriers and non-carriers of these SNPs. This finding supports the idea that these genetic variants may exert their effects more specifically in the central nervous system, particularly during active MS lesions.
Conclusion and Future Directions
This study highlights the potential role of genetic variants in determining the course of MS. The identification of SNPs in CPXM2, IGSF9B, and NLRP9 offers promising avenues for developing personalized medicine approaches in MS. By using these variants as biomarkers, clinicians could better predict disease progression and tailor treatment strategies for individual patients.
Further research is necessary to understand the precise molecular mechanisms by which these variants influence disease course. Additionally, studying larger patient cohorts and exploring gene-environment interactions will be crucial for validating these findings and translating them into clinical practice.
In summary, this study adds to the growing body of evidence that genetics play a crucial role not only in MS susceptibility but also in shaping the trajectory of the disease, opening the door to more targeted and effective treatments.
References:
Gil-Varea, E., Urcelay, E., Vilariño-Güell, C. et al. Exome sequencing study in patients with multiple sclerosis reveals variants associated with disease course. J Neuroinflammation 15, 265 (2018).
