Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Centre for Genomic Regulation (CRG) and Institute of Science and Technology (BIST), Barcelona, Spain.
Genome Biol. 2022 Apr 14;23(1):96. doi: 10.1186/s13059-022-02669-z.
Genome-wide association studies have identified 3p21.31 as the main risk locus for severe COVID-19, although underlying mechanisms remain elusive. We perform an epigenomic dissection of 3p21.31, identifying a CTCF-dependent tissue-specific 3D regulatory chromatin hub that controls the activity of several chemokine receptor genes. Risk SNPs colocalize with regulatory elements and are linked to increased expression of CCR1, CCR2 and CCR5 in monocytes and macrophages. As excessive organ infiltration of inflammatory monocytes and macrophages is a hallmark of severe COVID-19, our findings provide a rationale for the genetic association of 3p21.31 variants with elevated risk of hospitalization upon SARS-CoV-2 infection.
全基因组关联研究已经确定 3p21.31 是严重 COVID-19 的主要风险位点，尽管潜在机制仍不清楚。我们对 3p21.31 进行了表观基因组学分析，确定了一个依赖于 CTCF 的组织特异性 3D 调节染色质枢纽，该枢纽控制着几个趋化因子受体基因的活性。风险 SNP 与调节元件共定位，并与单核细胞和巨噬细胞中 CCR1、CCR2 和 CCR5 的表达增加相关。由于过度的炎症性单核细胞和巨噬细胞浸润是严重 COVID-19 的一个标志，我们的发现为 3p21.31 变异与 SARS-CoV-2 感染后住院风险升高的遗传关联提供了依据。
