The 3p21.31 locus is the most robust genomic region associated with COVID-19 severity. This locus contains a main chemokine receptor (CKR) cluster. 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 functions.
Laffranchi, M., Paraboschi, E., Bianchetto-Aguilera, F., Tamassia, N., Gasperini, S., Gardiman, E., et al. (2025). Neutrophils restricted contribution of CCRL2 genetic variants to COVID-19 severity. HELIYON, 11(1) [10.1016/j.heliyon.2024.e41267].
Neutrophils restricted contribution of CCRL2 genetic variants to COVID-19 severity
Invernizzi P.;
2025
Abstract
The 3p21.31 locus is the most robust genomic region associated with COVID-19 severity. This locus contains a main chemokine receptor (CKR) cluster. 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 functions.
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