Fine mapping and functional analysis of the multiple sclerosis risk gene CD6

Area of Science:

• Immunogenetics
• Neuroimmunology
• Molecular Biology

Background:

• CD6 is a validated risk gene for multiple sclerosis (MS), with prior association linked to SNP rs17824933.
• CD6 functions as a cell surface receptor crucial for T-cell activation, proliferation, and thymocyte differentiation.

Purpose of the Study:

• To investigate the association of CD6 gene variants with MS susceptibility.
• To explore the functional impact of identified MS-associated CD6 haplotypes on CD6 expression and cytokine secretion.

Main Methods:

• Haplotype tagging SNP (htSNP) screening of the CD6 gene locus using thirteen SNPs.
• Replication of a known GWAS SNP (rs650258) in a Spanish-Basque cohort (814 cases, 823 controls).
• Validation of top associated SNPs in an independent cohort (2265 MS patients, 2600 controls) and analysis of CD6 expression in immune cell subsets.

Main Results:

• Association of a haplotype comprising two non-synonymous SNPs (rs11230563 [R225W] and rs2074225 [A257V]) in the second SRCR domain with MS susceptibility (P=1×10⁻⁴).
• The protective haplotype (RA) demonstrated significantly higher CD6 surface expression on CD4+ naive, CD8+ naive, CD4+ central memory, CD8+ central memory, and natural killer T (NKT) cells.
• No significant changes in CD6 expression were observed in natural killer (NK) cells or effector memory T cell subsets.

Conclusions:

• A novel MS-associated CD6 risk haplotype significantly influences CD6 expression on CD4+ and CD8+ T cells.
• These findings highlight the role of specific CD6 variants in MS pathogenesis by modulating T-cell function.
• The identified haplotype provides a potential biomarker and therapeutic target for multiple sclerosis.