Abstract
Despite the high number of individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) symptoms worldwide, many exposed individuals remain asymptomatic and/or uninfected and seronegative. This could be explained by a combination of environmental (exposure), immunological (previous infection), epigenetic, and genetic factors. Aiming to identify genetic factors involved in immune response in symptomatic COVID-19 as compared to asymptomatic exposed individuals, we analyzed 83 Brazilian couples where one individual was infected and symptomatic while the partner remained asymptomatic and serum-negative for at least 6 months despite sharing the same bedroom during the infection. We refer to these as “discordant couples”. We performed whole-exome sequencing followed by a state-of-the-art method to call genotypes and haplotypes across the highly polymorphic major histocompatibility complex (MHC) region. The discordant partners had comparable ages and genetic ancestry, but women were overrepresented (65%) in the asymptomatic group. In the antigen-presentation pathway, we observed an association between HLA-DRB1 alleles encoding Lys at residue 71 (mostly DRB1*03:01 and DRB1*04:01) and DOB*01:02 with symptomatic infections and HLA-A alleles encoding 144Q/151R with asymptomatic seronegative women. Among the genes related to immune modulation, we detected variants in MICA and MICB associated with symptomatic infections. These variants are related to higher expression of soluble MICA and low expression of MICB. Thus, quantitative differences in these molecules that modulate natural killer (NK) activity could contribute to susceptibility to COVID-19 by downregulating NK cell cytotoxic activity in infected individuals but not in the asymptomatic partners.
Highlights
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, became a worldwide pandemic affecting millions of people and the leading cause of death in Brazil in 2020 and 2021
MICA promoter allele rs2596541/C is underrepresented in COVID-19[-] individuals when compared to symptomatic patients (p = 0.0034, odds ratios (ORs) = 1.9) and to the paired population sample (p = 0.0168) and overrepresented in the COVID-19[+] when compared to its paired population sample (p = 0.0331)
Our results suggest that genes related to immune modulation, mainly involved in natural killer (NK) cell killing activation/inhibition, harbor variants potentially contributing to infection resistance
Summary
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, became a worldwide pandemic affecting millions of people and the leading cause of death in Brazil in 2020 and 2021. Some variants and specific genome regions are related to disease severity and hospitalization (a proxy for disease severity), with different genome-wide association studies (GWASs) pointing to similar results Among these associated regions and variants, we may cite rs11385942 at 3p21.31, in the region encompassing genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, and XCR1, rs657152 at 9q34.2 (the ABO blood group), rs10735079 at 12q24.13, in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2, and OAS3), and rs74956615 at 19p13.2 (gene TYK2). One GWAS detected hits within the major histocompatibility complex (MHC), rs9380142 (HLA-G) and rs143334147 (CCHCR1) [5] While all these reported associations present p-values below the GWAS threshold (p < 10-8), the odds ratios (ORs) are very low (usually less than 1.5), and they cannot be considered predictive genomic markers of disease severity. Major efforts have been made to evaluate polymorphism and disease severity, usually by comparing hospitalized patients with a population-based sample (the normal control), but they do not evaluate COVID-19 resistance in exposed individuals
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
