Regulatory Noncoding and Predicted Pathogenic Coding Variants of <i>CCR5</i> Predispose to Severe COVID-19
Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. <i>CCR5</i> 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 <i>CCR5</i&...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-05-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/10/5372 |
| _version_ | 1797533412523769856 |
|---|---|
| author | Sueva Cantalupo Vito Alessandro Lasorsa Roberta Russo Immacolata Andolfo Giuseppe D’Alterio Barbara Eleni Rosato Giulia Frisso Pasquale Abete Gian Marco Cassese Giuseppe Servillo Ivan Gentile Carmelo Piscopo Matteo Della Monica Giuseppe Fiorentino Giuseppe Russo Pellegrino Cerino Carlo Buonerba Biancamaria Pierri Massimo Zollo Achille Iolascon Mario Capasso |
| author_facet | Sueva Cantalupo Vito Alessandro Lasorsa Roberta Russo Immacolata Andolfo Giuseppe D’Alterio Barbara Eleni Rosato Giulia Frisso Pasquale Abete Gian Marco Cassese Giuseppe Servillo Ivan Gentile Carmelo Piscopo Matteo Della Monica Giuseppe Fiorentino Giuseppe Russo Pellegrino Cerino Carlo Buonerba Biancamaria Pierri Massimo Zollo Achille Iolascon Mario Capasso |
| author_sort | Sueva Cantalupo |
| collection | DOAJ |
| description | Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. <i>CCR5</i> 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 <i>CCR5</i>, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (<i>P</i> ≤ 1 × 10<sup>−5</sup>) 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 <i>CCR5</i> expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with <i>CCR5</i> 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 <i>CCR5</i> 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 <i>CCR5</i>. |
| first_indexed | 2024-03-10T11:14:15Z |
| format | Article |
| id | doaj.art-7353faf6faa34d738f2c68e915642496 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:14:15Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7353faf6faa34d738f2c68e9156424962023-11-21T20:32:47ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-012210537210.3390/ijms22105372Regulatory Noncoding and Predicted Pathogenic Coding Variants of <i>CCR5</i> Predispose to Severe COVID-19Sueva Cantalupo0Vito Alessandro Lasorsa1Roberta Russo2Immacolata Andolfo3Giuseppe D’Alterio4Barbara Eleni Rosato5Giulia Frisso6Pasquale Abete7Gian Marco Cassese8Giuseppe Servillo9Ivan Gentile10Carmelo Piscopo11Matteo Della Monica12Giuseppe Fiorentino13Giuseppe Russo14Pellegrino Cerino15Carlo Buonerba16Biancamaria Pierri17Massimo Zollo18Achille Iolascon19Mario Capasso20Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80136 Napoli, ItalyDipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80136 Napoli, ItalyDipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80136 Napoli, ItalyDipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80136 Napoli, ItalyCEINGE Biotecnologie Avanzate, 80145 Napoli, ItalyDipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80136 Napoli, ItalyDipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80136 Napoli, ItalyCOVID Hospital, P.O.S. Anna e SS. Madonna della Neve di Boscotrecase, Ospedali Riuniti Area Vesuviana, 80042 Boscotrecase, ItalyCOVID Hospital, P.O.S. Anna e SS. Madonna della Neve di Boscotrecase, Ospedali Riuniti Area Vesuviana, 80042 Boscotrecase, ItalyDipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche, Università degli Studi di Napoli Federico II, 80131 Napoli, ItalyDipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, 80131 Napoli, ItalyMedical and Laboratory Genetics Unit, A.O.R.N. ‘Antonio Cardarelli’, 80131 Napoli, ItalyMedical and Laboratory Genetics Unit, A.O.R.N. ‘Antonio Cardarelli’, 80131 Napoli, ItalyAORN dei Colli Presidio Ospedaliero Cotugno, 80131 Napoli, ItalyUnità di Radiologia, Casa di Cura Villa dei Fiori, 80011 Acerra, ItalyIstituto Zooprofilattico Sperimentale del Mezzogiorno, 80055 Portici, ItalyIstituto Zooprofilattico Sperimentale del Mezzogiorno, 80055 Portici, ItalyIstituto Zooprofilattico Sperimentale del Mezzogiorno, 80055 Portici, ItalyDipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80136 Napoli, ItalyDipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80136 Napoli, ItalyDipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80136 Napoli, ItalyGenome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. <i>CCR5</i> 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 <i>CCR5</i>, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (<i>P</i> ≤ 1 × 10<sup>−5</sup>) 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 <i>CCR5</i> expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with <i>CCR5</i> 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 <i>CCR5</i> 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 <i>CCR5</i>.https://www.mdpi.com/1422-0067/22/10/5372<i>CCR5</i>COVID-19SARS-CoV-2SNPwhole exome sequencingGWAS |
| spellingShingle | Sueva Cantalupo Vito Alessandro Lasorsa Roberta Russo Immacolata Andolfo Giuseppe D’Alterio Barbara Eleni Rosato Giulia Frisso Pasquale Abete Gian Marco Cassese Giuseppe Servillo Ivan Gentile Carmelo Piscopo Matteo Della Monica Giuseppe Fiorentino Giuseppe Russo Pellegrino Cerino Carlo Buonerba Biancamaria Pierri Massimo Zollo Achille Iolascon Mario Capasso Regulatory Noncoding and Predicted Pathogenic Coding Variants of <i>CCR5</i> Predispose to Severe COVID-19 International Journal of Molecular Sciences <i>CCR5</i> COVID-19 SARS-CoV-2 SNP whole exome sequencing GWAS |
| title | Regulatory Noncoding and Predicted Pathogenic Coding Variants of <i>CCR5</i> Predispose to Severe COVID-19 |
| title_full | Regulatory Noncoding and Predicted Pathogenic Coding Variants of <i>CCR5</i> Predispose to Severe COVID-19 |
| title_fullStr | Regulatory Noncoding and Predicted Pathogenic Coding Variants of <i>CCR5</i> Predispose to Severe COVID-19 |
| title_full_unstemmed | Regulatory Noncoding and Predicted Pathogenic Coding Variants of <i>CCR5</i> Predispose to Severe COVID-19 |
| title_short | Regulatory Noncoding and Predicted Pathogenic Coding Variants of <i>CCR5</i> Predispose to Severe COVID-19 |
| title_sort | regulatory noncoding and predicted pathogenic coding variants of i ccr5 i predispose to severe covid 19 |
| topic | <i>CCR5</i> COVID-19 SARS-CoV-2 SNP whole exome sequencing GWAS |
| url | https://www.mdpi.com/1422-0067/22/10/5372 |
| work_keys_str_mv | AT suevacantalupo regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT vitoalessandrolasorsa regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT robertarusso regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT immacolataandolfo regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT giuseppedalterio regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT barbaraelenirosato regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT giuliafrisso regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT pasqualeabete regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT gianmarcocassese regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT giuseppeservillo regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT ivangentile regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT carmelopiscopo regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT matteodellamonica regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT giuseppefiorentino regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT giusepperusso regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT pellegrinocerino regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT carlobuonerba regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT biancamariapierri regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT massimozollo regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT achilleiolascon regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 AT mariocapasso regulatorynoncodingandpredictedpathogeniccodingvariantsoficcr5ipredisposetoseverecovid19 |