Human genetic determinants of COVID-19 in Brazil: challenges and future plans

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Abstract

COVID-19 pandemic represented a worldwide major challenge in different areas, and efforts undertaken by the scientific community led to the understanding of some of the genetic determinants that influence the different COVID-19 outcomes. In this paper, we review the studies about the role of human genetics in COVID-19 severity and how Brazilian studies also contributed to those findings. Rare variants in genes related to Inborn Errors of Immunity (IEI) in the type I interferons pathway, and its phenocopies, have been described as being causative of severe outcomes. IEI and its phenocopies are present in Brazil, not only in COVID-19 patients, but also in autoimmune conditions and severe reactions to yellow fever vaccine. In addition, studies focusing on common variants and GWAS studies encompassing worldwide patients have found several loci associated with COVID-19 severity. A GWAS study including only Brazilian COVID-19 patients identified a new locus 1q32.1 associated with COVID-19 severity. Thus, more comprehensive studies considering the Brazilian genomic diversity should be performed, since they can help to reveal not only what are the genetic determinants that contribute to the different outcomes for COVID-19 in the Brazilian population, but in the understanding of human genetics in different health conditions.

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Genomewide Association Study of Severe Covid-19 with Respiratory Failure

David Ellinghaus, Frauke Degenhardt, Luis Bujanda … (2020)

Abstract Background There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19. Methods We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case–control panels. Results We detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10−8) in the meta-analysis of the two case–control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.15×10−10; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P=4.95×10−8, respectively). At locus 3p21.31, the association signal spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-group–specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P=1.48×10−4) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P=1.06×10−5). Conclusions We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.)

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Genetic mechanisms of critical illness in COVID-19

Erola Pairo-Castineira, Sara Clohisey, Lucija Klaric (2021)

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.

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Presence of Genetic Variants Among Young Men With Severe COVID-19

Caspar van der Made, Annet Simons, Janneke H.M. Schuurs-Hoeijmakers … (2020)

Are genetic variants associated with severe coronavirus disease 2019 (COVID-19) in young male patients? In a case series that included 4 young male patients with severe COVID-19 from 2 families, rare loss-of-function variants of the X-chromosomal TLR7 were identified, with immunological defects in type I and II interferon production. These findings provide insights into the pathogenesis of COVID-19. Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19. Case series of pairs of brothers without medical history meeting the selection criteria of young (age T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7 , IFNB1 , and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod. In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19. This case series describes rare putative X-chromosomal loss-of-function variants associated with impaired peripheral mononuclear blood cell interferon signaling in 4 young male patients hospitalized with severe coronavirus disease 2019 (COVID-19) in the Netherlands.

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Author and article information

Contributors

Bibiana S. de Oliveira Fam:

ORCID: http://orcid.org/0000-0002-6654-6415

Role: conceivedRole: designed the studyRole: analyzed the dataRole: writingRole: reviewRole: read and approved the final version

Marilea Furtado Feira:

ORCID: http://orcid.org/0000-0001-7341-8457

Role: conceivedRole: designed the studyRole: analyzed the dataRole: writingRole: reviewRole: read and approved the final version

Nathan Araujo Cadore:

ORCID: http://orcid.org/0000-0001-6007-7147

Role: conceivedRole: designed the studyRole: analyzed the dataRole: writingRole: reviewRole: read and approved the final version

Renan Sbruzzi:

ORCID: http://orcid.org/0000-0003-2206-5502

Role: conceivedRole: designed the studyRole: analyzed the dataRole: writingRole: reviewRole: read and approved the final version

Tábita Hünemeier:

ORCID: http://orcid.org/0000-0002-3156-2079

Role: analyzed the dataRole: writingRole: reviewRole: read and approved the final version

Laurent Abel:

ORCID: http://orcid.org/0000-0001-7016-6493

Role: analyzed the dataRole: writingRole: reviewRole: read and approved the final version

Qian Zhang:

ORCID: http://orcid.org/0000-0002-9040-3289

Role: analyzed the dataRole: writingRole: reviewRole: read and approved the final version

Jean-Laurent Casanova:

ORCID: http://orcid.org/0000-0002-7782-4169

Role: analyzed the dataRole: writingRole: reviewRole: read and approved the final version

Fernanda Sales Luiz Vianna:

ORCID: http://orcid.org/0000-0001-6339-4869

Role: conceivedRole: designed the studyRole: analyzed the dataRole: writingRole: reviewRole: coordinateRole: funding acquisitionRole: read and approved the final version

Journal

Journal ID (nlm-ta): Genet Mol Biol

Journal ID (iso-abbrev): Genet Mol Biol

Journal ID (publisher-id): gmb

Title: Genetics and Molecular Biology

Publisher: Sociedade Brasileira de Genética

ISSN (Print): 1415-4757

ISSN (Electronic): 1678-4685

Publication date (Electronic, pub): 15 January 2024

Publication date (Electronic, collection): 2023

Volume: 46

Issue: 3 Suppl 1

Electronic Location Identifier: e20230128

Affiliations

[1 ]Hospital de Clínicas de Porto Alegre, Centro de Pesquisa Experimental, Laboratório de Medicina Genômica, Porto Alegre, RS, Brazil.

[2 ]Universidade Federal do Rio Grande do Sul, Instituto de Biociências, Departamento de Genética, Laboratório de Imunogenética, Programa de Pós-Graduação em Genética e Biologia Molecular, Porto Alegre, RS, Brazil.

[3 ]Instituto Nacional de Genética Médica Populacional (INaGeMP), Porto Alegre, RS, Brazil.

[4 ]Universidade de São Paulo, Instituto de Biociências, Departamento de Genética e Biologia Evolutiva, São Paulo, SP, Brazil.

[5 ]Institut de Biologia Evolutiva (Consejo Superior de Investigaciones Científicas/Universitat Pompeu Fabra), Barcelona, Spain.

[6 ]The Rockefeller University, Rockefeller Branch, St. Giles Laboratory of Human Genetics of Infectious Diseases, New York, NY, USA.

[7 ]Howard Hughes Medical Institute, New York, NY, USA.

[8 ]Laboratory of Human Genetics of Infectious Diseases, Imagine Institute, Paris, France.

[9 ]University Paris Cité, Imagine Institute, Paris, France.

[10 ]Necker Hospital for Sick Children, Department of Pediatrics, Paris, France.

Author notes

Associate Editor: : Lavínia Schüler-Faccini

Send correspondence to Fernanda Sales Luiz Vianna. Hospital de Clínicas de Porto Alegre, Centro de Pesquisa Experimental, Laboratório de Medicina Genômica, R. Ramiro Barcelos, 2350, 90035-007, Porto Alegre, RS, Brazil. E-mail: fslvianna@gmail.com

Conflict of Interest: The authors declare that there is no conflict of interest that could be perceived as prejudicial to the impartiality of the reported research.