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

Bernard S. Stikker; Grégoire Stik; Antoinette F. van Ouwerkerk; Lianne Trap; Salvatore Spicuglia; Rudi W. Hendriks; Ralph Stadhouders

doi:10.1186/s13059-022-02669-z

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

Bernard S. Stikker, Grégoire Stik, Antoinette F. van Ouwerkerk, Lianne Trap, Salvatore Spicuglia, Rudi W. Hendriks, Ralph Stadhouders^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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.

Original language	English
Article number	96
Journal	Genome Biology
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s13059-022-02669-z
Publication status	Published - 14 Apr 2022

Bibliographical note

Funding Information:
B.S. and R.W.H. are supported by Dutch Lung Foundation grant 4.1.18.226. G.S. was supported by the ‘Fundación Científica de la Asociación Española Contra el Cáncer’. R.S. is supported by an Erasmus MC Fellowship, a Dutch Lung Foundation Junior Investigator grant (4.2.19.041JO) and a VIDI grant (09150172010068) from the Dutch Research Council (NWO). A.F.v.O. was supported by a postdoctoral fellowship from the Foundation Recherche Médicale. S.S. was supported by an Agence National pour la Recherche” grant (ANR-18-CE12-0019).

Publisher Copyright: © 2022, The Author(s).

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

abstract = "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.",

author = "Stikker, {Bernard S.} and Gr{\'e}goire Stik and {van Ouwerkerk}, {Antoinette F.} and Lianne Trap and Salvatore Spicuglia and Hendriks, {Rudi W.} and Ralph Stadhouders",

note = "Funding Information: B.S. and R.W.H. are supported by Dutch Lung Foundation grant 4.1.18.226. G.S. was supported by the {\textquoteleft}Fundaci{\'o}n Cient{\'i}fica de la Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer{\textquoteright}. R.S. is supported by an Erasmus MC Fellowship, a Dutch Lung Foundation Junior Investigator grant (4.2.19.041JO) and a VIDI grant (09150172010068) from the Dutch Research Council (NWO). A.F.v.O. was supported by a postdoctoral fellowship from the Foundation Recherche M{\'e}dicale. S.S. was supported by an Agence National pour la Recherche” grant (ANR-18-CE12-0019). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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AU - Hendriks, Rudi W.

AU - Stadhouders, Ralph

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AB - 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.

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

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