Severe COVID-19-associated variants linked to chemokine receptor gene control in monocytes and macrophages

Bernard Stikker (1) , Grégoire Stik (2) , Antoinette van Ouwerkerk (3) , Lianne Trap (1) , Salvatore Spicuglia (3) , Rudi Hendriks (1) , Ralph Stadhouders (1)

1 Erasmus MC - Erasmus University Medical Center [Rotterdam]
2 UPF - Universitat Pompeu Fabra [Barcelona]
3 TAGC - Theories and Approaches of Genomic Complexity

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.

Mots clés: SARS-CoV-2; COVID-19; 3p21.31; GWAS; Monocyte; Macrophage; Chemokine receptor; 3D genome organization; CTCF; Gene regulation

Domaines: Médecine humaine et pathologie; Immunologie

Bernard Stikker, Grégoire Stik, Antoinette van Ouwerkerk, Lianne Trap, Salvatore Spicuglia, et al.. Severe COVID-19-associated variants linked to chemokine receptor gene control in monocytes and macrophages. Genome Biology, 2022, 23 (1), pp.96. ⟨10.1186/s13059-022-02669-z⟩. ⟨hal-03685514⟩