Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908.
Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033.
Hum Mutat. 2021 Oct;42(10):1208-1214. doi: 10.1002/humu.24244. Epub 2021 Jun 29.
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.
全基因组关联研究已经确定了与 9p21.3 上的神经胶质瘤风险相关的 SNP，但这种关联的生物学机制尚不清楚。我们检验了这样一个假设，即 9p21.3 上的一个功能性 SNP 会影响增强子的活性，导致附近基因的表达发生改变。我们考虑了与位于假定增强子内的 9p21.3 哨兵 SNP rs634537 处于连锁不平衡状态的所有 SNP。含有 rs1537372 的增强子表现出与荧光素酶活性的等位基因特异性效应。在 GBM 细胞系中，该增强子的缺失与 CDKN2B-AS1 的表达减少相关。使用非疾病脑组织样本进行的表达数量性状基因座分析表明，rs1537372 是 CDKN2B-AS1 的一个一致显著的 eQTL。此外，我们对神经祖细胞中生成的 Hi-C 数据的分析表明，包含 rs1537372 的诱饵区域与 CDKN2B-AS1 启动子相互作用。这些数据表明，位于 9p21.3 风险位点的 SNP rs1537372 是一个调节 CDKN2B-AS1 表达的功能性变体。
