1. Increased THEMIS First Exon Usage in CD4+ T-Cells Is Associated with a Genotype that Is Protective against Multiple Sclerosis.
- Author
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Davies JL, Thompson S, Kaur-Sandhu H, Sawcer S, Coles A, Ban M, and Jones J
- Subjects
- Adult, Alleles, CD4-Positive T-Lymphocytes metabolism, Exons genetics, Female, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Intracellular Signaling Peptides and Proteins biosynthesis, Male, Middle Aged, Multiple Sclerosis immunology, Multiple Sclerosis pathology, Polymorphism, Single Nucleotide, Protein Isoforms biosynthesis, Protein Isoforms genetics, Genetic Predisposition to Disease, Intracellular Signaling Peptides and Proteins genetics, Multiple Sclerosis genetics, Quantitative Trait Loci genetics
- Abstract
Multiple sclerosis is an autoimmune disease of the central nervous system. Genome wide association studies have identified over 100 common variants associated with multiple sclerosis, the majority of which implicate immunologically relevant genes, particularly those involved in T-cell development. SNP rs13204742 at the THEMIS/PTPRK locus is one such variant. Here, we have demonstrated mutually exclusive use of exon 1 and 2 amongst 16 novel THEMIS isoforms. We also show inverse correlation between THEMIS expression in human CD4+ T-cells and dosage of the multiple sclerosis risk allele at rs13204742, driven by reduced expression of exon 1- containing isoforms. In silico analysis suggests that this may be due to cell-specific, allele-dependent binding of the transcription factors FoxP3 and/or E47. Research exploring the functional implications of GWAS variants is important for gaining an understanding of disease pathogenesis, with the ultimate aim of identifying new therapeutic targets.
- Published
- 2016
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