Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, United States.
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, United States.
Elife. 2019 Jul 25;8:e42720. doi: 10.7554/eLife.42720.
Murine studies have linked TGF-β signaling to emphysema, and human genome-wide association studies (GWAS) studies of lung function and COPD have identified associated regions near genes in the TGF-β superfamily. However, the functional regulatory mechanisms at these loci have not been identified. We performed the largest GWAS of emphysema patterns to date, identifying 10 GWAS loci including an association peak spanning a 200 kb region downstream from . Integrative analysis of publicly available eQTL, DNaseI, and chromatin conformation data identified a putative functional variant, rs1690789, that may regulate expression in human fibroblasts. Using chromatin conformation capture, we confirmed that the region containing rs1690789 contacts the promoter in fibroblasts, and CRISPR/Cas-9 targeted deletion of a ~ 100 bp region containing rs1690789 resulted in decreased expression in primary human lung fibroblasts. These data provide novel mechanistic evidence linking genetic variation affecting the TGF-β pathway to emphysema in humans.
小鼠研究将 TGF-β 信号与肺气肿联系起来，人类全基因组关联研究（GWAS）对肺功能和 COPD 的研究确定了 TGF-β 超家族基因附近的相关区域。然而，这些基因座的功能调节机制尚未确定。我们进行了迄今为止最大的肺气肿模式 GWAS，确定了 10 个 GWAS 基因座，包括一个跨越. 下游 200kb 区域的关联峰。对公开可用的 eQTL、DNaseI 和染色质构象数据的综合分析确定了一个可能的功能变体 rs1690789，它可能调节人成纤维细胞中的 表达。使用染色质构象捕获，我们证实包含 rs1690789 的区域在成纤维细胞中与 启动子接触，并且包含 rs1690789 的约 100bp 区域的 CRISPR/Cas-9 靶向缺失导致原代人肺成纤维细胞中 表达降低。这些数据提供了新的机制证据，将影响 TGF-β 通路的遗传变异与人类肺气肿联系起来。
