Increased THEMIS First Exon Usage in CD4+ T-Cells Is Associated with a Genotype that Is Protective against Multiple Sclerosis

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.

多发性硬化（Multiple Sclerosis）是一种中枢神经系统自身免疫性疾病。全基因组关联研究（Genome Wide Association Studies, GWAS）已鉴定出100余种与多发性硬化相关的常见遗传变异，其中绝大多数关联到免疫相关基因，尤其是参与T细胞发育的基因。位于THEMIS/PTPRK基因座的单核苷酸多态性（Single Nucleotide Polymorphism, SNP）rs13204742即为其中一类变异。本研究证实，在16种新型THEMIS异构体中，外显子1与外显子2存在互斥选择性使用模式。此外，我们发现人类CD4阳性T细胞（CD4+ T-cells）中THEMIS的表达水平与rs13204742位点多发性硬化风险等位基因的剂量呈负相关，这一关联由含外显子1的异构体表达水平下调所介导。计算机模拟（in silico）分析显示，这一现象可能源于转录因子FoxP3和/或E47的细胞特异性、等位基因依赖性结合。解析全基因组关联研究变异体的功能效应，对于阐明疾病发病机制、最终发掘全新治疗靶点具有重要意义。