Abstract
OBJECTIVE: To study the influence of the Abelson helper integration site 1 (AHI1) locus associated with MS susceptibility on CD4(+) T cell function. METHODS: We characterized the chromatin state of T cells in the MS-associated AHI1 linkage disequilibrium (LD) block. The expression and the role of the AHI1 variant were examined in T cells from genotyped healthy subjects who were recruited from the PhenoGenetic Project, and the function of AHI1 was explored using T cells from Ahi1 knockout mice. RESULTS: Chromatin state analysis reveals that the LD block containing rs4896153, which is robustly associated with MS susceptibility (odds ratio 1.15, p = 1.65 × 10(-13)), overlaps with strong enhancer regions that are present in human naive and memory CD4(+) T cells. Relative to the rs4896153(A) protective allele, the rs4896153(T) susceptibility allele is associated with decreased AHI1 mRNA expression, specifically in naive CD4(+) T cells (p = 1.73 × 10(-74), n = 213), and we replicate this effect in an independent set of subjects (p = 2.5 × 10(-9), n = 32). Functional studies then showed that the rs4896153(T) risk variant and the subsequent decreased AHI1 expression were associated with reduced CD4(+) T cell proliferation and a specific differentiation into interferon gamma (IFNγ)-positive T cells when compared with the protective rs4896153(A) allele. This T cell phenotype was also observed in murine CD4(+) T cells with genetic deletion of Ahi1. CONCLUSIONS: Our findings suggest that the effect of the AHI1 genetic risk for MS is mediated, in part, by enhancing the development of proinflammatory IFNγ(+) T cells that have previously been implicated in MS and its mouse models.