A hypermorphic SP1-binding CD24 variant associates with risk and progression of multiple sclerosis.
A hypermorphic SP1-binding CD24 variant associates with risk and progression of multiple sclerosis.
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发表时间：
2012
影响因子：
2.2
通讯作者：
Lizhong Wang;Runhua Liu;Dongling Li;Shili Lin;Xianfeng Fang;Grant Backer;Mandy L Kain;Kottil Rammoham;P. Zheng;Yang Liu
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文献类型：
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作者：
Lizhong Wang;Runhua Liu;Dongling Li;Shili Lin;Xianfeng Fang;Grant Backer;Mandy L Kain;Kottil Rammoham;P. Zheng;Yang Liu
多发性硬化症(MS)的危险等位基因已被发现。然而，对于大多数风险等位基因来说，遗传变异如何影响发病机制在很大程度上仍不清楚。通过对CD24启动子区域的直接测序，我们发现了CD24启动子上的7个新的单核苷酸多态。通过935名对照组和76 4名MS患者的关联研究，发现了一个由3个SNPs组成的多态单倍型(P=0.001，优势比1.3)。该变异还与多发性硬化症进展更快有关(P=0.016，对数列检验)。在风险等位基因杂合子的细胞中，染色质免疫沉淀显示风险等位基因与转录因子SP1特异结合，该转录因子是该变异体高形态启动子活性选择性所必需的。在MS患者中，CD24转录水平与SP1结合变异体呈剂量依赖关系(P=7x10(-4))。我们的数据揭示了SP1介导的转录调控在MS发病机制中的潜在作用。
A large number of risk alleles have been identified for multiple sclerosis (MS). However, how genetic variations may affect pathogenesis remains largely unknown for most risk alleles. Through direct sequencing of CD24 promoter region, we identified a cluster of 7 new single nucleotide polymorphisms in the CD24 promoter. A hypermorphic haplotype consisting of 3 SNPs was identified through association studies consisting of 935 control and 764 MS patients (P=0.001, odds ratio 1.3). The variant is also associated with more rapid progression of MS (P=0.016, log rank test). In cells that are heterozygous for the risk allele, chromatin immunoprecipitation revealed that risk allele specifically bind to a transcription factor SP1, which is selectively required for the hypermorphic promoter activity of the variant. In MS patients, the CD24 transcript levels associate with the SP1-binding variant in a dose-dependent manner (P=7x10(-4)). Our data revealed a potential role for SP1-mediated transcriptional regulation in MS pathogenesis.