Neutrophils restricted contribution of CCRL2 genetic variants to COVID-19 severity
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...
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Elsevier
2025-01-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844024172982 |
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| author | Mattia Laffranchi Elvezia Maria Paraboschi Francisco Bianchetto-Aguilera Nicola Tamassia Sara Gasperini Elisa Gardiman Arianna Piserà Annalisa Del Prete Pietro Invernizzi Angela Gismondi Alberto Mantovani Marco A. Cassatella Rosanna Asselta Silvano Sozzani |
| author_facet | Mattia Laffranchi Elvezia Maria Paraboschi Francisco Bianchetto-Aguilera Nicola Tamassia Sara Gasperini Elisa Gardiman Arianna Piserà Annalisa Del Prete Pietro Invernizzi Angela Gismondi Alberto Mantovani Marco A. Cassatella Rosanna Asselta Silvano Sozzani |
| author_sort | Mattia Laffranchi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5769c2ed355447cfa601068938902305 |
| institution | Kabale University |
| issn | 2405-8440 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj-art-5769c2ed355447cfa6010689389023052025-01-17T04:50:42ZengElsevierHeliyon2405-84402025-01-01111e41267Neutrophils restricted contribution of CCRL2 genetic variants to COVID-19 severityMattia Laffranchi0Elvezia Maria Paraboschi1Francisco Bianchetto-Aguilera2Nicola Tamassia3Sara Gasperini4Elisa Gardiman5Arianna Piserà6Annalisa Del Prete7Pietro Invernizzi8Angela Gismondi9Alberto Mantovani10Marco A. Cassatella11Rosanna Asselta12Silvano Sozzani13Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy; Corresponding author. Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, ItalyDepartment of Medicine, Section of General Pathology, University of Verona, 37134, Verona, ItalyDepartment of Medicine, Section of General Pathology, University of Verona, 37134, Verona, ItalyDepartment of Medicine, Section of General Pathology, University of Verona, 37134, Verona, ItalyDepartment of Medicine, Section of General Pathology, University of Verona, 37134, Verona, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDivision of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo Dei Tintori, Monza, Italy; Department of Medicine and Surgery, University of Milano-Bicocca, Monza, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, ItalyDepartment of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; The William Harvey Research Institute, Queen Mary University of London, London, United KingdomDepartment of Medicine, Section of General Pathology, University of Verona, 37134, Verona, ItalyDepartment of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Corresponding author. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, ItalyThe 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.http://www.sciencedirect.com/science/article/pii/S2405844024172982GWASCOVID-19ChIP-seqNeutrophilsSNPeQTL |
| spellingShingle | Mattia Laffranchi Elvezia Maria Paraboschi Francisco Bianchetto-Aguilera Nicola Tamassia Sara Gasperini Elisa Gardiman Arianna Piserà Annalisa Del Prete Pietro Invernizzi Angela Gismondi Alberto Mantovani Marco A. Cassatella Rosanna Asselta Silvano Sozzani Neutrophils restricted contribution of CCRL2 genetic variants to COVID-19 severity Heliyon GWAS COVID-19 ChIP-seq Neutrophils SNP eQTL |
| title | Neutrophils restricted contribution of CCRL2 genetic variants to COVID-19 severity |
| title_full | Neutrophils restricted contribution of CCRL2 genetic variants to COVID-19 severity |
| title_fullStr | Neutrophils restricted contribution of CCRL2 genetic variants to COVID-19 severity |
| title_full_unstemmed | Neutrophils restricted contribution of CCRL2 genetic variants to COVID-19 severity |
| title_short | Neutrophils restricted contribution of CCRL2 genetic variants to COVID-19 severity |
| title_sort | neutrophils restricted contribution of ccrl2 genetic variants to covid 19 severity |
| topic | GWAS COVID-19 ChIP-seq Neutrophils SNP eQTL |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024172982 |
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