A Functional Variant on 9p21.3 Related to Glioma Risk Affects Enhancer Activity and Modulates Expression of CDKN2B-AS1.
A Functional Variant on 9p21.3 Related to Glioma Risk Affects Enhancer Activity and Modulates Expression of CDKN2B-AS1.
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DOI：
10.1002/humu.24244
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发表时间：
2021-10
期刊：
影响因子：
3.9
通讯作者：
Casey G
中科院分区：
文献类型：
--
作者：
Ali MW;Patro CPK;Devall M;Dampier CH;Plummer SJ;Kuscu C;Adli M;Lai RK;Casey G
全基因组关联研究已经确定了9p21.3上与胶质瘤风险相关的SNP，但这种关联的生物学机制尚不清楚。我们测试了9p21.3上的功能性SNP影响增强子活性，导致附近基因表达改变的假设。我们认为所有SNP均与定位到推定增强子的9p21.3前哨SNP rs634537连锁不平衡。含有rs1537372的增强子对荧光素酶活性表现出等位基因特异性作用。GBM细胞系中该增强子的缺失与CDKN2B-AS1表达降低相关。使用非患病脑样品的表达定量性状位点分析显示rs1537372是CDKN2B-AS1的一致显著eQTL。此外，我们对神经祖细胞中产生的Hi-C数据的分析表明，含有rs1537372的诱饵区与CDKN2B-AS1启动子相互作用。这些数据表明rs1537372是9p21.3风险位点的SNP，是调节CDKN2B-AS1表达的功能性变体。
Genome‐wide association studies have identified SNPs associated with glioma risk on 9p21.3, but biological mechanisms underlying this association are unknown. We tested the hypothesis that a functional SNP on 9p21.3 affects activity of an enhancer, causing altered expression of nearby genes. We considered all SNPs in linkage disequilibrium with the 9p21.3 sentinel SNP rs634537 that mapped to putative enhancers. An enhancer containing rs1537372 exhibited allele‐specific effects on luciferase activity. Deletion of this enhancer in GBM cell lines correlated with decreased expression of CDKN2B‐AS1. Expression quantitative trait loci analysis using non‐diseased brain samples showed rs1537372 to be a consistently significant eQTL for CDKN2B‐AS1. Additionally, our analysis of Hi‐C data generated in neural progenitor cells showed that the bait region containing rs1537372 interacted with the CDKN2B‐AS1 promoter. These data suggest rs1537372, a SNP at the 9p21.3 risk locus, is a functional variant that modulates expression of CDKN2B‐AS1.
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