Neutrophils restricted contribution of CCRL2 genetic variants to COVID-19 severity

The 3p21.31 locus, which locus contains a chemokine receptor (CKR) cluster, is the most robust genomic region associated with COVID-19 severity. We tested expression quantitative trait loci (eQTL) targeting the 3p21.31 CKR cluster linked to COVID-19 hospitalization in Europeans from the COVID-19 HGI meta-analysis. Among these, CCRL2, a key regulator of neutrophil trafficking, was targeted by neutrophil-restricted eQTLs. We confirmed these eQTLs in an Italian COVID-19 cohort. Haplotype analysis revealed a link between an increased CCRL2 expression and COVID-19 severity and hospitalization. By the exposure of neutrophils to a TLR8 ligand, reflecting a viral infection, we revealed specific chromatin domains within the 3p21.31 locus exclusive to neutrophils. In addition, the identified variants mapped within these regions altered the binding motif of neutrophils expressed transcription factors. These results support that CCRL2 eQTL variants contribute to the risk of severe COVID-19 by selectively affecting neutrophil’s function