rs11808092 — EVI5

EVI5 Q612H — A Molecular Relay That Redirects Immune Cell Traffic

The EVI5 gene¹¹ EVI5 gene
Ecotropic Viral Integration Site 5; originally identified as a retroviral integration site that could activate cellular oncogenes, now recognised as a multifunctional regulator of cell division and vesicle trafficking encodes a protein that belongs to the TBC (Tre-2/Bub2/Cdc16) domain family of GTPase-activating proteins. Its primary cellular job is to activate Rab11, a small GTPase that coordinates the recycling of membrane vesicles during cell division and intracellular transport. EVI5 also stabilises proteins that control cell-cycle re-entry, functioning as an oncogenic driver in some cancers. rs11808092 introduces a missense change in EVI5's coiled-coil domain — one amino acid swapped — that rewires more than half the protein's binding partner network²² rewires more than half the protein's binding partner network
Q612H variant associates with 16 exclusive protein partners absent from wild-type EVI5 and loses associations with several normal partners, reshaping 55% of the interactome. The downstream consequence is an altered interaction with sphingosine 1-phosphate lyase (SGPL1), a key enzyme governing where immune cells can migrate — directly implicating this single amino acid change in multiple sclerosis risk.

The Mechanism

EVI5 contains two principal functional regions: an N-terminal TBC domain³³ TBC domain
TBC = Tre-2/Bub2/Cdc16 homology domain; a conserved catalytic module found in GTPase-activating proteins that switch small GTPases from their active GTP-bound state to their inactive GDP-bound state that acts on Rab11, and a C-terminal coiled-coil domain⁴⁴ coiled-coil domain
A coiled-coil is a structural motif where two or more alpha helices wind around each other; it is a common protein–protein interaction interface that mediates protein–protein interactions. The Q612H substitution sits within this coiled-coil region and exchanges a polar, uncharged glutamine for a positively charged histidine. Structural modelling shows that this charge swap alters the surface hydrophobicity of the domain⁵⁵ alters the surface hydrophobicity of the domain
Computational models predict changes in the electrostatic surface of the coiled-coil that reorient which partners can dock, creating a new docking interface for SGPL1⁶⁶ SGPL1
Sphingosine 1-phosphate lyase — the enzyme that irreversibly degrades sphingosine 1-phosphate (S1P). Its activity is the dominant force creating the S1P concentration gradient between lymphoid organs and blood.

Sphingosine 1-phosphate⁷⁷ Sphingosine 1-phosphate
An intercellular lipid mediator whose steep gradient — high in blood, low in lymphoid organs — functions as a compass that guides lymphocytes from lymph nodes into circulation (S1P) is the signal that licenses T cells to leave lymph nodes and patrol the body. SGPL1 maintains this gradient by degrading S1P in tissues. By acquiring SGPL1 as a novel binding partner, the Q612H variant likely sequesters or modulates SGPL1 activity⁸⁸ sequesters or modulates SGPL1 activity
The interaction with SGPL1 could alter local S1P degradation, disrupting the gradient that controls lymphocyte egress from secondary lymphoid organs, dysregulating the trafficking of autoreactive T cells into the central nervous system — the central pathogenic event in multiple sclerosis. Notably, the drug class fingolimod (Gilenya)⁹⁹ fingolimod (Gilenya)
A first-in-class S1P receptor modulator approved for relapsing MS that traps lymphocytes in lymph nodes, reducing CNS infiltration works by mimicking this very same pathway, underscoring the biological plausibility of the EVI5–SGPL1 connection.

The Evidence

EVI5 emerged as an MS susceptibility locus from the landmark 2007 IMSGC genome-wide association study¹⁰¹⁰ landmark 2007 IMSGC genome-wide association study
The International Multiple Sclerosis Genetics Consortium enrolled >12,000 individuals of European ancestry and identified multiple non-HLA loci; EVI5 was among the first confirmed that scanned the entire genome in thousands of MS patients. The specific rs11808092 Q612H missense variant was then characterised as a non-synonymous coding change almost entirely in linkage disequilibrium¹¹¹¹ linkage disequilibrium
LD measures how often two variants are inherited together; near-complete LD (r²≈1) means they are nearly interchangeable as markers with the intronic tag SNP rs11809700, the strongest signal at the locus.

Hoppenbrouwers et al. (2008)¹²¹² Hoppenbrouwers et al. (2008)
Confirmed EVI5 as a novel MS risk gene in a Dutch isolated population, with replication in 1,318 Canadian MS patients (OR 1.15) demonstrated that EVI5 is genuinely causal rather than a bystander at the locus, with odds ratios of 1.9–2.01 in a genetically isolated population where confounders are minimised.

The largest synthesis came from a 2016 meta-analysis¹³¹³ 2016 meta-analysis
Pooled 16 independent case-control studies from 12 publications comprising 4,600 MS cases and 6,612 controls, predominantly Caucasian populations that assembled 16 independent case-control studies (4,600 MS cases, 6,612 controls) and confirmed rs11808092 is significant across every genetic model tested: per-allele OR 1.17 (95% CI 1.10–1.24), heterozygous OR 1.16, and homozygous OR 1.37. The dose-dependent pattern across CC → AC → AA genotypes is consistent with an additive risk architecture.

At the molecular level, Cabeza-Fernandez et al. (2015)¹⁴¹⁴ Cabeza-Fernandez et al. (2015)
Human Molecular Genetics study used pull-down proteomics and structural modelling to characterise the Q612H interactome change; PMID 26433934 showed that Q612H rewires 55% of the EVI5 protein interaction network, with gene ontology analysis revealing strong enrichment in lipid metabolism — precisely the pathway involved in S1P gradient generation. This study bridges the genetic signal and mechanism in a way rarely achieved for GWAS loci.

Practical Implications

EVI5 rs11808092 contributes modestly but measurably to multiple sclerosis risk. MS is a complex disease with strong HLA contributions (HLA-DR15 is the dominant risk factor), and rs11808092 represents one of many non-HLA loci that cumulatively shape individual risk. Carrying one or two A alleles does not predict MS with high certainty — approximately 95% of A-allele carriers never develop MS — but it shifts the baseline. The risk elevation is analogous to intermediate-effect cardiovascular loci: meaningful in aggregate risk calculations, not deterministic in isolation.

What is actionable: MS is one of the few neurological diseases where early treatment substantially changes long-term outcomes. Disease-modifying therapies are most effective when started at or before the first clinical event. Individuals with this genotype and a family history of MS or unexplained neurological symptoms (vision changes, limb numbness, imbalance, extreme fatigue) should discuss the genetic context with their neurologist. Given the S1P mechanism, the theoretical plausibility of vitamin D and omega-3 supplementation (both modulate immune cell trafficking and neuroinflammation) is especially relevant for A allele carriers — though this connection is not yet proven for rs11808092 specifically.

Interactions

The EVI5 locus sits within a larger GWAS region (chromosome 1p22) spanning GFI1, EVI5, RPL5, and FAM69A. Tag-SNP analysis¹⁵¹⁵ Tag-SNP analysis
Tested 21 putative MS susceptibility variants in the region to map the causal signal has shown that rs11809700 (intronic) and rs11808092 (Q612H) are in near-complete LD and together capture the full regional MS association — the other nearby SNPs do not add independent information.

EVI5 rs11808092 acts through S1P-mediated T-cell trafficking, a pathway mechanistically separate from but clinically parallel to HLA-DRB1*15:01 (tagged by rs3135388), which acts through antigen presentation. Individuals carrying both the high-risk HLA haplotype and the EVI5 A allele accumulate risk from two independent immunological pathways — antigen recognition and lymphocyte mobilisation — potentially magnifying susceptibility beyond what either confers alone, though formal epistasis between these loci has not been reported.