Unraveling the Genetic Link: How EVI5 Variants Influence Multiple Sclerosis Risk Through Lipid Metabolism
Multiple sclerosis (MS) is a complex immune-mediated neurodegenerative disease affecting the central nervous system (CNS), characterized by demyelination, axonal damage. While the etiology of MS is not fully understood, it is widely believed to result from an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified genomic regions associated with MS risk, with the major histocompatibility complex (MHC) locus on chromosome 6p21.3 being the most prominent. However, identifying the causative variants within these regions remains challenging due to the pervasive linkage disequilibrium (LD) across the genome.
In a study, Didonna et al. (2015) have focused on the locus at chromosome 1p22.1, which has been repeatedly associated with MS susceptibility in various populations. The study aimed to fine-map this locus and identify the most plausible disease risk gene. The authors identified the ecotropic viral integration site 5 (EVI5) gene as the strongest candidate within this locus. Specifically, they investigated the effects of a non-synonymous single-nucleotide polymorphism (SNP) within EVI5 that could influence MS risk by altering the EVI5 protein's interactome, particularly with proteins involved in lipid metabolism.
Fine Mapping of the EVI5 Locus
The researchers conducted a meta-analysis of 13 published MS datasets, including genotypes from 13,799 cases and 24,252 controls. They identified the SNP rs11809700, located in the ninth intron of EVI5, as the top associated variant with MS risk (P = 1.09 × 10^-15, OR = 1.17). This finding was consistent with previous studies that had also implicated EVI5 as the disease gene in this locus. The authors extended their analysis to exonic SNPs and identified three variants, two of which (rs2391199 and rs11808092) promote non-synonymous substitutions (I336V and Q612H, respectively).
Interestingly, the Q612H variant (rs11808092) showed almost complete LD with the top intronic SNP (r^2 = 0.932), suggesting a strong link between this exonic variant and MS susceptibility. The authors hypothesized that this variant might alter the EVI5 protein's function by changing the superficial hydrophobicity patterns of its coiled-coil (CC) domain, potentially affecting its interaction with other proteins.
EVI5 Protein Interactome and Lipid Metabolism
To test this hypothesis, the researchers conducted immunoprecipitation assays followed by mass spectrometry to identify the protein interactors of EVI5 and its variants (WT-EVI5, I336V-EVI5, and Q612H-EVI5). They discovered that the Q612H variant significantly altered the EVI5 interactome, with 16 exclusive interactors linked to lipid metabolism. Among these, sphingosine 1-phosphate lyase (SGPL1) emerged as a novel interactor of Q612H-EVI5. SGPL1 is a key enzyme involved in the creation of the sphingosine-1-phosphate (S1P) gradient, which regulates immune cell trafficking—a process highly relevant to MS pathology.
The interaction between Q612H-EVI5 and SGPL1 was validated through reciprocal co-immunoprecipitation experiments, confirming the specificity of this interaction. The authors noted that while this interaction suggests a potential link between EVI5 variants and lipid metabolism in MS, further studies are needed to elucidate the functional consequences of this binding on the S1P pathway and overall MS risk.
Implications and Future Directions
The study by Didonna et al. provides compelling evidence that the EVI5 gene, particularly the Q612H variant, plays a crucial role in MS susceptibility by modulating protein interactions related to lipid metabolism. This discovery opens new avenues for understanding the genetic underpinnings of MS and highlights the importance of lipid metabolism in the disease's pathogenesis.
Future research should focus on exploring the broader implications of the SGPL1-EVI5 interaction, particularly in the context of S1P signaling and immune regulation. Additionally, the potential impact of this interaction on the efficacy of S1P-targeting therapies, such as fingolimod, could provide valuable insights for personalized treatment strategies in MS.
In conclusion, the identification of EVI5 as a key player in MS risk underscores the complexity of the disease and the need for continued research into the genetic and molecular mechanisms driving its development. By unraveling these intricate networks, researchers can pave the way for more targeted and effective interventions for those affected by MS.
References:
Didonna, A., Isobe, N., Caillier, S. J., Li, K. H., Burlingame, A. L., Hauser, S. L., ... & Oksenberg, J. R. (2015). A non-synonymous single-nucleotide polymorphism associated with multiple sclerosis risk affects the EVI5 interactome. Human molecular genetics, 24(24), 7151-7158.
