Genome-wide association studies have identified 3p21.31 as the main risk locus for severe disease in COVID-19 patients, although underlying biological mechanisms remain elusive. We performed a comprehensive epigenomic dissection of the 3p21.31 locus, identifying a CTCF-dependent tissue-specific 3D regulatory chromatin hub that controls the activity of several tissue-homing chemokine receptor (CCR) genes in monocytes and macrophages. Risk SNPs colocalized with regulatory elements and were 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.

中文翻译：

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与单核细胞和巨噬细胞中趋化因子受体基因控制相关的严重 COVID-19 相关变体

全基因组关联研究已将 3p21.31 确定为 COVID-19 患者严重疾病的主要风险位点，尽管潜在的生物学机制仍然难以捉摸。我们对 3p21.31 基因座进行了全面的表观基因组解剖，确定了一个 CTCF 依赖性组织特异性 3D 调节染色质中枢，它控制着单核细胞和巨噬细胞中几种组织归巢趋化因子受体 (CCR) 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 的表达增加有关。由于炎症性单核细胞和巨噬细胞的过度器官浸润是严重 COVID-19 的标志，我们的研究结果为 3p21.31 变体与 SARS-CoV-2 感染后住院风险升高之间的遗传关联提供了理论依据。