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Article

Regulatory Noncoding and Predicted Pathogenic Coding Variants of CCR5 Predispose to Severe COVID-19

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Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80136 Napoli, Italy
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CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy
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COVID Hospital, P.O.S. Anna e SS. Madonna della Neve di Boscotrecase, Ospedali Riuniti Area Vesuviana, 80042 Boscotrecase, Italy
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Dipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy
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Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy
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Medical and Laboratory Genetics Unit, A.O.R.N. ‘Antonio Cardarelli’, 80131 Napoli, Italy
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AORN dei Colli Presidio Ospedaliero Cotugno, 80131 Napoli, Italy
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Unità di Radiologia, Casa di Cura Villa dei Fiori, 80011 Acerra, Italy
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Istituto Zooprofilattico Sperimentale del Mezzogiorno, 80055 Portici, Italy
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Dipartimento di Medicina, Chirurgia e Odontoiatria “Scuola Medica Salernitana”, Università di Salerno, 84081 Baronissi, Italy
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Author to whom correspondence should be addressed.
Academic Editors: Jordi Pérez-Tur and Fernando Cardona Serrate
Int. J. Mol. Sci. 2021, 22(10), 5372; https://doi.org/10.3390/ijms22105372
Received: 23 April 2021 / Revised: 12 May 2021 / Accepted: 18 May 2021 / Published: 20 May 2021
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. View Full-Text
Keywords: CCR5; COVID-19; SARS-CoV-2; SNP; whole exome sequencing; GWAS CCR5; COVID-19; SARS-CoV-2; SNP; whole exome sequencing; GWAS
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MDPI and ACS Style

Cantalupo, S.; Lasorsa, V.A.; Russo, R.; Andolfo, I.; D’Alterio, G.; Rosato, B.E.; Frisso, G.; Abete, P.; Cassese, G.M.; Servillo, G.; Gentile, I.; Piscopo, C.; Della Monica, M.; Fiorentino, G.; Russo, G.; Cerino, P.; Buonerba, C.; Pierri, B.; Zollo, M.; Iolascon, A.; Capasso, M. Regulatory Noncoding and Predicted Pathogenic Coding Variants of CCR5 Predispose to Severe COVID-19. Int. J. Mol. Sci. 2021, 22, 5372. https://doi.org/10.3390/ijms22105372

AMA Style

Cantalupo S, Lasorsa VA, Russo R, Andolfo I, D’Alterio G, Rosato BE, Frisso G, Abete P, Cassese GM, Servillo G, Gentile I, Piscopo C, Della Monica M, Fiorentino G, Russo G, Cerino P, Buonerba C, Pierri B, Zollo M, Iolascon A, Capasso M. Regulatory Noncoding and Predicted Pathogenic Coding Variants of CCR5 Predispose to Severe COVID-19. International Journal of Molecular Sciences. 2021; 22(10):5372. https://doi.org/10.3390/ijms22105372

Chicago/Turabian Style

Cantalupo, Sueva, Vito A. Lasorsa, Roberta Russo, Immacolata Andolfo, Giuseppe D’Alterio, Barbara E. Rosato, Giulia Frisso, Pasquale Abete, Gian M. Cassese, Giuseppe Servillo, Ivan Gentile, Carmelo Piscopo, Matteo Della Monica, Giuseppe Fiorentino, Giuseppe Russo, Pellegrino Cerino, Carlo Buonerba, Biancamaria Pierri, Massimo Zollo, Achille Iolascon, and Mario Capasso. 2021. "Regulatory Noncoding and Predicted Pathogenic Coding Variants of CCR5 Predispose to Severe COVID-19" International Journal of Molecular Sciences 22, no. 10: 5372. https://doi.org/10.3390/ijms22105372

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