Allele-Specific Chromatin Remodeling in the ZPBP2/GSDMB/ORMDL3 Locus Associated with the Risk of Asthma and Autoimmune Disease
Allele-Specific Chromatin Remodeling in the ZPBP2/GSDMB/ORMDL3 Locus Associated with the Risk of Asthma and Autoimmune Disease
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DOI：
10.1016/j.ajhg.2009.08.007
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发表时间：
2009-09-11
影响因子：
9.8
通讯作者：
Naumova, Anna K.
中科院分区：
文献类型：
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作者：
Verlaan, Dominique J.;Berlivet, Soizik;Naumova, Anna K.
染色体 17q12-q21 区域中的常见 SNP 会改变哮喘、I 型糖尿病、原发性胆汁性肝硬化和克罗恩病的风险。我们和其他人之前的报告已将疾病相关的遗传变异与人淋巴母细胞系 (LCL) 中 GSDMB 和 ORMDL3 转录物表达的变化联系起来。这些变体还改变其他转录本的调节，这种全域顺式调节效应表明涉及长程染色质相互作用的机制。在这里，我们进一步剖析与疾病相关的单倍型，并通过遗传和功能分析相结合来识别假定的因果 DNA 变异。首先，对该区域进行高通量重测序并对潜在候选变体进行基因分型。接下来，约鲁巴 HapMap LCL 中等位基因表达差异的额外映射使我们能够将顺式调控差异的基础精细映射到少数候选功能变体。功能分析确定了核小体分布的等位基因特异性差异、与绝缘子蛋白 CTCF 的等位基因特异性关联以及 rs12936231 的弱启动子活性。总体而言，这项研究表明一种常见疾病等位基因与 CTCF 结合和核小体占据的变化相关，导致全域顺式调节改变。最后，在三个独立的基于家庭的队列中观察到哮喘和顺式调节单倍型之间存在很强的关联（p = 1.78 x 10(-8)）。这项研究证明了需要多个平行等位基因特异性工具来研究非编码疾病变异和人类疾病相关单倍型的功能精细定位。
Common SNPs in the chromosome 17q12-q21 region alter the risk for asthma, type I diabetes, primary biliary cirrhosis, and Crohn disease. Previous reports by us and others have linked the disease-associated genetic variants with changes in expression of GSDMB and ORMDL3 transcripts in human lymphoblastoid cell lines (LCLs). The variants also alter regulation of other transcripts, and this domain-wide cis-regulatory effect suggests a mechanism involving long-range chromatin interactions. Here, we further dissect the disease-linked haplotype and identify putative causal DNA variants via a combination of genetic and functional analyses. First, high-throughput resequencing of the region and genotyping of potential candidate variants were performed. Next, additional mapping of allelic expression differences in Yoruba HapMap LCLs allowed us to fine-map the basis of the cis-regulatory differences to a handful of candidate functional variants. Functional assays identified allele-specific differences in nucleosome distribution, an allele-specific association with the insulator protein CTCF, as well as a weak promoter activity for rs12936231. Overall, this study shows a common disease allele linked to changes in CTCF binding and nucleosome occupancy leading to altered domain-wide cis-regulation. Finally, a strong association between asthma and cis-regulatory haplotypes was observed in three independent family-based cohorts (p = 1.78 x 10(-8)). This study demonstrates the requirement of multiple parallel allele-specific tools for the investigation of noncoding disease variants and functional fine-mapping of human disease-associated haplotypes.