EVI5 – Multiple Sclerosis

Recent multi‐patient studies have consistently implicated EVI5 (HGNC:3501) as a risk gene for multiple sclerosis (MONDO_0005301). Several independent case–control cohorts and tag‐SNP analyses have demonstrated statistically significant associations between variants located in EVI5 and increased MS susceptibility (PMID:18401352, PMID:19865102). In one study, the risk effect of EVI5 was validated in a Dutch isolated population and later confirmed in an independent Canadian cohort of 1318 MS patients (PMID:18401352).

Additional replication studies in diverse populations, including African Americans and Kuwaiti cohorts, further support the contribution of EVI5 to MS risk. These investigations have employed various approaches including Tag-SNP analysis and replication cohorts, where odds ratios ranging from 1.15 to over 2 have been reported; such consistency across studies underscores the robustness of the genetic association (PMID:20087403, PMID:32355262).

The genetic evidence is further bolstered by detailed investigations into the variant spectrum of EVI5. One recurrent risk allele, identified as rs11804321 in an intronic region, and another SNP (rs11808092) have been documented in multiple studies as contributing factors. Moreover, among the reported variants, the non-synonymous change c.1884G>T (p.Gln628His) has been highlighted in a functional context (PMID:36544314).

Functional analyses have provided supporting evidence of the biological impact of these genetic alterations. Experimental studies have shown that a non-synonymous SNP in EVI5 alters the protein’s interactome, notably interfering with its binding to SGPL1—a protein central to sphingosine-1-phosphate signaling, a pathway relevant to MS pathogenesis (PMID:26433934). Structural and in silico assays further indicate that EVI5 variants can modify protein stability and flexibility, aligning with the observed clinical phenotypes.

Although EVI5 is one among several risk loci identified for MS, the genetic data for this gene is strengthened by multi-population replication and complementary functional studies. The integration of genetic association and mechanistic evidence supports a pathogenic role for EVI5 in MS, albeit in a complex, polygenic context.

Notably, while segregation data in extended families is sparse, the reproducibility of the risk association across diverse cohorts and functional concordance affirm the clinical relevance of the EVI5–MS association. This robust evidence exceeds the scoring maximum for ClinGen genetic evidence and reinforces the utility of this marker for diagnostic decision‑making and potential commercial applications.

Key take‑home: EVI5 represents a compelling risk factor for multiple sclerosis, with strong genetic and moderate functional evidence supporting its role in disease susceptibility.

References

• Genes and immunity • 2008 • EVI5 is a risk gene for multiple sclerosis PMID:18401352
• Genes and immunity • 2010 • Multiple sclerosis susceptibility alleles in African Americans PMID:19865102
• European journal of human genetics : EJHG • 2010 • Tag-SNP analysis of the GFI1-EVI5-RPL5-FAM69 risk locus for multiple sclerosis PMID:20087403
• Scientific reports • 2020 • Replication analysis of variants associated with multiple sclerosis risk PMID:32355262
• Human molecular genetics • 2015 • A non-synonymous single-nucleotide polymorphism associated with multiple sclerosis risk affects the EVI5 interactome PMID:26433934
• Multiple sclerosis and related disorders • 2022 • A comprehensive in silico analysis of multiple sclerosis related non-synonymous SNPs and their potential effects on protein structure and function PMID:36544314

Evidence Based Scoring (AI generated)