MHC Variants Associated With Symptomatic Versus Asymptomatic SARS-CoV-2 Infection in Highly Exposed Individuals
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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.
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SciScore for 10.1101/2021.04.21.21255872: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources This allowed excluding 7 couples where the asymptomatic partner was found to have IgA or IgG antibodies against SARS-CoV-2. SARS-CoV-2suggested: NoneSoftware and Algorithms Sentences Resources Reads were aligned to the human reference GRCh38 using BWA (https://github.com/lh3/bwa/tree/master/bwakit). BWAsuggested: (BWA, RRID:SCR_010910)We also called genotypes using GATK HaplotypeCaller (version 4.0.9). GATKsuggested: (GATK, RRID:SCR_001876)Results from OddPub: We did not detect open data. We also did not detect open code. …
SciScore for 10.1101/2021.04.21.21255872: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources This allowed excluding 7 couples where the asymptomatic partner was found to have IgA or IgG antibodies against SARS-CoV-2. SARS-CoV-2suggested: NoneSoftware and Algorithms Sentences Resources Reads were aligned to the human reference GRCh38 using BWA (https://github.com/lh3/bwa/tree/master/bwakit). BWAsuggested: (BWA, RRID:SCR_010910)We also called genotypes using GATK HaplotypeCaller (version 4.0.9). GATKsuggested: (GATK, RRID:SCR_001876)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:However, few studies have focused on the genetics of resistance against SARS-CoV-2 infection due to limitations in controlling for exposure. Previous reports on host genetic factors with resistance to COVID-19 have investigated SARS-CoV-2 receptors such as the angiotensin-converting enzyme 2 (ACE2), the transmembrane protease serine-type 2 (TMPRSS2), glucose-regulated protein 78-kDa (GRP78), and the extracellular matrix metalloproteinase inducer or cluster of differentiation 147 (CD147) [reviewed by 18]. Recent observations showed that secondary transmission among close household contacts was 53%19. Furthermore, recently, the Brazilian media reported that both sibs from 7 pairs of monozygotic adult twins died from SARS-CoV-2 infection within a few days of difference. These observations support the hypothesis that genetic factors, which are largely unknown in SARS-CoV-2, influence infection susceptibility and resistance. Spouses of infected and symptomatic COVID-19 patients sharing the same bedroom without protective measures represent an efficient approach to identify and ascertain resistant individuals highly exposed to the same viral strain of SARS-CoV-2. Here, we investigated 86 discordant couples, in which one was symptomatic, and the partner remained asymptomatic and serum negative. Since we collected all samples in the first semester of 2020, all couples were likely exposed to the same or closely related viral strains 20. Our study suggests that genes of innate and adap...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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