Autoimmune neurologic diseases
To date, 233 genetic variants have been associated with multiple sclerosis (MS) susceptibility. We prioritized 8 MS susceptibility genes that are highly expressed in human Th17 cells polarized in vitro and focused on one, sestrin 3 (SESN3) gene. We found that the rs4409785 risk allele (C) associated with MS risk also leads to a significant decrease in SESN3 RNA expression in naïve CD4+ T cells (p=1.58E-16). We characterized chromatin state of four T-cell subsets, naïve, memory, T helper 17 and regulatory CD4+ T cells using the Roadmap Epigenomics data and found that the rs4409785 SNP overlaps with quiescent chromatin state in all four T cell subsets. Furtheremore, using DNA methylation data from CD4+ T cells of MS patients, we observed a genome-wide significant cis-mQTL effect between rs4409785 risk allele (C) and hypermethylation of cg26564895 (p=8.65E-7), which is located close to the SESN3 transcription start site
Analysis of SESN3 gene expression in naïve and memory CD4+ T cells in healthy, untreated and glatiramer acetate (GA)-treated MS patients (n=196) shows that SESN3 expression is decreased in memory T cells from untreated MS patients compared to healthy controls, however SESN3 expression is induced in MS patients that received GA-treatment. These data suggest that SESN3 may be involved in downregulating the autoimmune response in MS. Functional studies using conditional knockout mice in addition to gene deletion strategies in human T cells are ongoing to further characterize the function of SESN3 in the regulation T cell pathogenicity.