Regulatory Noncoding and Predicted Pathogenic Coding Variants of CCR5 Predispose to Severe COVID-19
Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe COVID-19...
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| Veröffentlicht in: | International journal of molecular sciences 2021-05, Vol.22 (10), p.5372 |
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| creator | Cantalupo, Sueva Lasorsa, Vito Alessandro Russo, Roberta Andolfo, Immacolata D’Alterio, Giuseppe Rosato, Barbara Eleni Frisso, Giulia Abete, Pasquale Cassese, Gian Marco Servillo, Giuseppe Gentile, Ivan Piscopo, Carmelo Della Monica, Matteo Fiorentino, Giuseppe Russo, Giuseppe Cerino, Pellegrino Buonerba, Carlo Pierri, Biancamaria Zollo, Massimo Iolascon, Achille Capasso, Mario |
| description | Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (P ≤ 1 × 10−5) at the 3p21.31 locus in public GWAS datasets (6406 COVID-19 hospitalized patients and 902,088 controls) with gene expression data from 208 lung tissues, Hi-C, and Chip-seq data. Through whole exome sequencing (WES), we explored rare coding variants in 147 severe COVID-19 patients. We identified three SNPs (rs9845542, rs12639314, and rs35951367) associated with severe COVID-19 whose risk alleles correlated with low CCR5 expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with CCR5 gene in lung tissues and was confirmed to be associated with severe COVID-19 in two independent datasets. We also identified a rare coding variant (rs34418657) associated with the risk of developing severe COVID-19. Our results suggest a biological role of CCR5 in the progression of COVID-19 as common and rare genetic variants can increase the risk of developing severe COVID-19 by affecting the functions of CCR5. |
| doi_str_mv | 10.3390/ijms22105372 |
| format | Article |
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CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (P ≤ 1 × 10−5) at the 3p21.31 locus in public GWAS datasets (6406 COVID-19 hospitalized patients and 902,088 controls) with gene expression data from 208 lung tissues, Hi-C, and Chip-seq data. Through whole exome sequencing (WES), we explored rare coding variants in 147 severe COVID-19 patients. We identified three SNPs (rs9845542, rs12639314, and rs35951367) associated with severe COVID-19 whose risk alleles correlated with low CCR5 expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with CCR5 gene in lung tissues and was confirmed to be associated with severe COVID-19 in two independent datasets. We also identified a rare coding variant (rs34418657) associated with the risk of developing severe COVID-19. Our results suggest a biological role of CCR5 in the progression of COVID-19 as common and rare genetic variants can increase the risk of developing severe COVID-19 by affecting the functions of CCR5.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms22105372</identifier><identifier>PMID: 34065289</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Binding sites ; Biological effects ; CCR5 protein ; Chromosome 3 ; Chromosomes ; Coronaviruses ; COVID-19 ; Datasets ; Disease ; Gene expression ; Genetic diversity ; Genome-wide association studies ; Genomes ; HIV ; Hospitalization ; Human immunodeficiency virus ; Infections ; Loci ; Lungs ; Nucleotides ; Risk ; Risk factors ; Severe acute respiratory syndrome coronavirus 2 ; Single-nucleotide polymorphism</subject><ispartof>International journal of molecular sciences, 2021-05, Vol.22 (10), p.5372</ispartof><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). 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CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (P ≤ 1 × 10−5) at the 3p21.31 locus in public GWAS datasets (6406 COVID-19 hospitalized patients and 902,088 controls) with gene expression data from 208 lung tissues, Hi-C, and Chip-seq data. Through whole exome sequencing (WES), we explored rare coding variants in 147 severe COVID-19 patients. We identified three SNPs (rs9845542, rs12639314, and rs35951367) associated with severe COVID-19 whose risk alleles correlated with low CCR5 expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with CCR5 gene in lung tissues and was confirmed to be associated with severe COVID-19 in two independent datasets. We also identified a rare coding variant (rs34418657) associated with the risk of developing severe COVID-19. 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Gian Marco</au><au>Servillo, Giuseppe</au><au>Gentile, Ivan</au><au>Piscopo, Carmelo</au><au>Della Monica, Matteo</au><au>Fiorentino, Giuseppe</au><au>Russo, Giuseppe</au><au>Cerino, Pellegrino</au><au>Buonerba, Carlo</au><au>Pierri, Biancamaria</au><au>Zollo, Massimo</au><au>Iolascon, Achille</au><au>Capasso, Mario</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulatory Noncoding and Predicted Pathogenic Coding Variants of CCR5 Predispose to Severe COVID-19</atitle><jtitle>International journal of molecular sciences</jtitle><date>2021-05-20</date><risdate>2021</risdate><volume>22</volume><issue>10</issue><spage>5372</spage><pages>5372-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (P ≤ 1 × 10−5) at the 3p21.31 locus in public GWAS datasets (6406 COVID-19 hospitalized patients and 902,088 controls) with gene expression data from 208 lung tissues, Hi-C, and Chip-seq data. Through whole exome sequencing (WES), we explored rare coding variants in 147 severe COVID-19 patients. We identified three SNPs (rs9845542, rs12639314, and rs35951367) associated with severe COVID-19 whose risk alleles correlated with low CCR5 expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with CCR5 gene in lung tissues and was confirmed to be associated with severe COVID-19 in two independent datasets. 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| ispartof | International journal of molecular sciences, 2021-05, Vol.22 (10), p.5372 |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Binding sites Biological effects CCR5 protein Chromosome 3 Chromosomes Coronaviruses COVID-19 Datasets Disease Gene expression Genetic diversity Genome-wide association studies Genomes HIV Hospitalization Human immunodeficiency virus Infections Loci Lungs Nucleotides Risk Risk factors Severe acute respiratory syndrome coronavirus 2 Single-nucleotide polymorphism |
| title | Regulatory Noncoding and Predicted Pathogenic Coding Variants of CCR5 Predispose to Severe COVID-19 |
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