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.
Asthma is a complex and heterogeneous chronic inflammatory disease of the airways. Alongside environmental factors, asthma susceptibility is strongly influenced by genetics. Given its high prevalence and our incomplete understanding of the mechanisms underlying disease susceptibility, asthma is frequently studied in genome‐wide association studies (GWAS), which have identified thousands of genetic variants associated with asthma development. Virtually all these genetic variants reside in non‐coding genomic regions, which has obscured the functional impact of asthma‐associated variants and their translation into disease‐relevant mechanisms. Recent advances in genomics technology and epigenetics now offer methods to link genetic variants to gene regulatory elements embedded within non‐coding regions, which have started to unravel the molecular mechanisms underlying the complex (epi)genetics of asthma. Here, we provide an integrated overview of (epi)genetic variants associated with asthma, focusing on efforts to link these disease associations to biological insight into asthma pathophysiology using state‐of‐the‐art genomics methodology. Finally, we provide a perspective as to how decoding the genetic and epigenetic basis of asthma has the potential to transform clinical management of asthma and to predict the risk of asthma development.
Genome-wide association studies have identified 3p21.31 as the main risk locus for severe symptoms and hospitalization in COVID-19 patients. To elucidate the mechanistic basis of this genetic association, we performed a comprehensive epigenomic dissection of the 3p21.31 locus. Our analyses pinpoint activating variants in regulatory regions of the chemokine receptor-encoding CCR1 gene as potentially pathogenic by enhancing infiltration of monocytes and macrophages into the lungs of patients with severe COVID-19.
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