Critically-ill COVID-19 susceptibility geneCCR3shows natural selection in sub-Saharan Africans

Abstract

AbstractThe prevalence of COVID-19 critical illness varies across ethnicities, with recent studies suggesting that genetic factors may contribute to this variation. The aim of this study was to investigate natural selection signals of genes associated with critically-ill COVID-19 in sub-Saharan Africans. Severe COVID-19 SNPs were obtained from the HGI website. Selection signals were assessed in 661 sub-Sahara Africans from 1000 Genomes Project using integrated haplotype score (iHS), cross-population extended haplotype homozygosity (xpEHH), and fixation index (Fst). Allele frequency trajectory analysis of ancient DNA samples were used to validate the existing of selection in sub-Sahara Africans. We also used Mendelian randomization to decipher the correlation between natural selection and critically-ill COVID-19. We identified thatCCR3exhibited significant natural selection signals in sub-Sahara Africans. Within theCCR3gene, rs17217831-A showed both high iHS (Standardized iHS = 2) and high XP-EHH (Standardized XP-EHH = 2.5) in sub-Sahara Africans. Allele frequency trajectory ofCCR3rs17217831-A revealed natural selection occurring in the recent 1,500 years. Natural selection resulted in increasedCCR3expression in sub-Sahara Africans. Mendelian Randomization provided evidence that increased bloodCCR3expression and eosinophil counts lowered the risk of critically ill COVID-19. Our findings suggest that sub-Saharan Africans are less vulnerable to critically ill COVID-19 due to natural selection and identifyCCR3as a potential novel therapeutic target.