Transcript specific regulation of expression influences susceptibility to multiple sclerosis
Transcript specific regulation of expression influences susceptibility to multiple sclerosis
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DOI：
10.1038/s41431-019-0569-0
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发表时间：
2020-01-13
影响因子：
5.2
通讯作者：
Sawcer, Stephen
中科院分区：
文献类型：
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作者：
Ban, Maria;Liao, Wenjia;Sawcer, Stephen
全基因组关联研究（GWAS）已经确定了超过100个含有单核苷酸变异（SNV）的基因座，这些变异会影响多发性硬化症（MS）的发病风险。这些基因座中的大多数位于基因组的非编码调节区，这些区域在免疫细胞中具有活性，因此被认为通过改变关键免疫基因的表达来改变风险。为了探索这一假设，我们筛选基因侧翼MS相关的变异的等位基因特异性表达（ASE）的证据，通过量化转录的编码变异与MS相关的SNV连锁不平衡。总的来说，我们能够识别并成功分析来自106名MS患者和105名对照的CD 4+和CD 8 + T细胞中的200种编码变体（来自112个基因）。这些编码变体中的五十六种（来自43个基因）在一种或两种细胞类型中显示出统计学显著的ASE证据。例如，在Lck相互作用跨膜衔接子1基因（LIME 1）中，我们能够证明在两种细胞类型中，MS相关变体rs 2256814增加了一些转录本的表达，同时减少了其他转录本的表达。在来自另外一组独立的96例病例和93例对照的CD 4+细胞中，我们能够使用qPCR（p = 5 × 10（-24））复制这种SNV对替代性LIME 1转录物平衡的影响。因此，我们的数据表明，GWAS鉴定的一些MS相关SNV可能通过扭曲替代转录物的平衡而不是通过改变基因表达的总体水平来影响风险。
Genome-wide association studies (GWAS) have identified over 100 loci containing single nucleotide variants (SNVs) that influence the risk of developing multiple sclerosis (MS). Most of these loci lie in non-coding regulatory regions of the genome that are active in immune cells and are therefore thought to modify risk by altering the expression of key immune genes. To explore this hypothesis we screened genes flanking MS-associated variants for evidence of allele specific expression (ASE) by quantifying the transcription of coding variants in linkage disequilibrium with MS-associated SNVs. In total, we were able to identify and successfully analyse 200 such coding variants (from 112 genes) in both CD4+ and CD8+ T cells from 106 MS patients and 105 controls. Fifty-six of these coding variants (from 43 genes) showed statistically significant evidence of ASE in one or both cell types. In the Lck interacting transmembrane adaptor 1 gene (LIME1), for example, we were able to show that in both cell types, the MS-associated variant rs2256814 increased the expression of some transcripts while simultaneously reducing the expression of other transcripts. In CD4+ cells from an additional independent set of 96 cases and 93 controls we were able to replicate the effect of this SNV on the balance of alternate LIME1 transcripts using qPCR (p = 5 x 10(-24)). Our data thus indicate that some of the MS-associated SNVs identified by GWAS likely exert their effects on risk by distorting the balance of alternate transcripts rather than by changing the overall level of gene expression.