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

Abstract

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^-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 <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>.