GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Government, PTS, 18016 Granada, Spain.
Unit of Chronic Inflammatory Diseases, Institute for Environmental Medicine, Karolinska Institutet, 171 67 Solna, Sweden.
Int J Mol Sci. 2018 Aug 8;19(8):2331. doi: 10.3390/ijms19082331.
is a susceptibility gene for several systemic autoimmune diseases in several populations. Using the genome-wide association study (GWAS) data from Europeans (EUR) and African Americans (AA), we performed an extensive fine mapping of ankyrin repeats 1 (). To increase the SNP density, we used imputation followed by univariate and conditional analysis, combined with a haplotypic and expression quantitative trait locus (eQTL) analysis. The data from Europeans showed that the associated region was restricted to a minimal and dependent set of SNPs covering introns two and three, and exon two. In AA, the signal found in the Europeans was split into two independent effects. All of the major risk associated SNPs were eQTLs, and the risks were associated with an increased gene expression. Functional annotation analysis revealed the enrichment of repressive B cell epigenomic marks (EZH2 and H3K27me3) and a strong enrichment of splice junctions. Furthermore, one eQTL located in intron two, rs13106926, was found within the binding site for RUNX3, a transcriptional activator. These results connect the local genome topography, chromatin structure, and the regulatory landscape of with co-transcriptional splicing of exon two. Our data defines a minimal set of risk associated eQTLs predicted to be involved in the expression of modulated through epigenetic regulation and splicing. These findings allow us to suggest that the increased expression of will have an impact on B-cell mediated disease pathways.
是几种人群中几种系统性自身免疫疾病的易感基因。我们利用欧洲人（EUR）和非裔美国人（AA）的全基因组关联研究（GWAS）数据，对锚蛋白重复序列 1（）进行了广泛的精细定位。为了增加 SNP 密度，我们使用了 imputation 技术，随后进行了单变量和条件分析，结合了连锁不平衡和表达数量性状基因座（eQTL）分析。欧洲人的数据表明，相关区域仅限于覆盖内含子 2 和 3 以及外显子 2 的一组最小和依赖的 SNP。在 AA 中，在欧洲人身上发现的信号分为两个独立的效应。所有主要的风险相关 SNP 都是 eQTL，风险与基因表达增加相关。功能注释分析显示了抑制性 B 细胞表观遗传标记（EZH2 和 H3K27me3）的富集，以及剪接的强烈富集。此外，一个位于内含子 2 中的 eQTL，rs13106926，位于转录激活因子 RUNX3 的结合位点内。这些结果将局部基因组拓扑结构、染色质结构和 的调控景观与外显子 2 的共转录剪接联系起来。我们的数据定义了一组最小的风险相关 eQTL，这些 eQTL 被预测参与了通过表观遗传调控和剪接调节的 表达。这些发现使我们能够假设，的表达增加将对 B 细胞介导的疾病途径产生影响。
