Genetic variability in COVID-19-related genes in the Brazilian population (preprint)

ABSTRACT

SARS-CoV-2 employs the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane serine protease (TMPRSS2) to infect human lung cells. Previous studies have suggested that different host genetic backgrounds in ACE2 and TMPRSS2 could contribute to differences in the rate of infection or severity of COVID-19. Recent studies also showed that variants in 15 genes related to type I interferon immunity to influenza virus could predispose to life-threatening COVID-19 pneumonia. Additional genes (SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, XCR1, IL6, CTSL, ABO, and FURIN) and HLA alleles have also been implicated in response to infection with SARS-CoV-2. Currently, Brazil has recorded the third-highest number of COVID-19 patients worldwide. We aim to investigate the genetic variation present in COVID-19-related genes in the Brazilian population. We analysed 27 candidate genes and HLA alleles in 954 admixed Brazilian exomes. We used the information available in two public databases (http//www.bipmed.org and http//abraom.ib.usp.br/), and additional exomes from individuals born in southeast Brazil, the region with the highest number of COVID-19 patients in the country. Variant allele frequencies were compared with the 1000 Genomes Project phase 3 (1KGP) and the gnomAD databases. We found 395 non-synonymous variants; of these, 325 were also found in the 1000 Genome Project phase 3 (1KGP) and/or gnomAD. Six of these variants were previously reported as putatively influencing the rate of infection or clinical prognosis for COVID-19. The remaining 70 variants were identified exclusively in the Brazilian sample, with a mean allele frequency of 0.0025. In silico prediction of the impact in protein function revealed that three of these rare variants were pathogenic. Furthermore, we identified HLA alleles that were previously associated with COVID-19 response at loci DQB1 and DRB1. Our results showed genetic variability common to other populations, but also rare and ultra-rare variants exclusively found in the Brazilian population. These findings could potentially lead to differences in the rate of infection or response to infection by SARS-CoV-2 and should be further investigated in patients with the disease.