LY9 – Systemic Lupus Erythematosus

This summary synthesizes evidence from multiple studies demonstrating that variants in LY9 (HGNC:6730) are significantly associated with systemic lupus erythematosus (SLE) (MONDO_0007915). Family‐based association studies in UK and Canadian cohorts have identified both promoter and coding region variants with statistically significant findings (p = 0.00209 [PMID:18216865]). The reported evidence includes segregation across several families and altered immune profiles in affected individuals, highlighting the relevance of LY9 in SLE pathogenesis.

Genetic evidence focuses on a nonsynonymous coding change in exon 8. Specifically, the variant c.1805G>A (p.Val602Met) has been identified and is associated with altered phosphorylation motifs that likely influence downstream signaling. This variant, along with other genetic markers in the LY9 locus, has been observed to segregate in affected families, thus reinforcing the genetic contribution of LY9 to SLE ([PMID:18216865]).

Functional assessments further support the role of LY9 in disease mechanism. Studies have shown that the Val602Met change disrupts SH2 domain binding with the adaptor protein SAP, resulting in significant alterations in T-cell activation. In cell-based models, altered expression levels were correlated with shifts in immune cell populations, such as increased CD8+ memory T cells and decreased CD4+ naïve T cells, which are consistent with immune dysregulation seen in SLE ([PMID:26221972]).

While a separate study investigating similar genetic factors in rheumatoid arthritis did not observe an association, the specificity of the LY9 association with SLE is underscored by the functional data. This conflicting evidence in RA serves to further delineate the role of LY9 in SLE rather than a generalized autoimmune predisposition ([PMID:19714582]).

Integrating the genetic and experimental data reinforces the conclusion that LY9 is a key contributor to SLE through mechanisms involving aberrant T-cell regulation. The replication of findings across multi-patient studies and functional assays not only substantiates the association but also provides mechanistic insight that enriches diagnostic decision-making and may inform future targeted research.

Key take‑home sentence: The strong genetic and functional evidence linking the LY9 variant c.1805G>A (p.Val602Met) to altered T‑cell activity establishes its clinical utility in understanding and potentially managing systemic lupus erythematosus.

References

• Genes and immunity • 2008 • Association of LY9 in UK and Canadian SLE families PMID:18216865
• Immunology • 2015 • A polymorphism in a phosphotyrosine signalling motif of CD229 (Ly9, SLAMF3) alters SH2 domain binding and T‑cell activation PMID:26221972
• Arthritis and rheumatism • 2009 • Rheumatoid arthritis does not share most of the newly identified systemic lupus erythematosus genetic factors PMID:19714582

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