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Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection

Astrid Marchal et al. HGG Adv. .

Abstract

Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Keywords: COVID-19; HLA; association; asymptomatic infection; population stratification.

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Conflict of interest statement

Declaration of interests E.T.C., K.M.S.B., and A.B. are employees of Helix.

Figures

Figure 1
Figure 1
Study design (A) Description of the two cohorts and definitions of asymptomatic and symptomatic cases. ICU, intensive care unit. (B) List of HLA-wide association studies and meta-analyses performed.
Figure 2
Figure 2
HLA-B∗15:01 is not enriched in asymptomatic cases (A) Allele frequency and 95% confidence intervals in the US prospective cohort European subgroups. (B) Allele frequency and 95% CIs in the CHGE European sample. (C) Allele frequency and 95% CIs in individuals highly exposed to SARS-CoV-2 who never tested positive (“Resistors,” n = 291) and in children with SARS-CoV-2 infection complicated by multisystem inflammatory syndrome (“MIS-C,” n = 235) from the European CHGE sample. (D) Allele frequency and 95% CIs in Middle Eastern (ME) individuals from the CHGE cohort (Symptomatic, n = 895; Asymptomatic, n = 37).
Figure 3
Figure 3
HLA-B∗15:01 in the SARS-CoV-2 Human Challenge Characterisation Study: Symptoms and HLA-B genotypes for 18 infected participants Daily total symptom score was calculated using self-reported symptom diaries three times daily. Daily total symptom scores are displayed in the heatmap, ranging from green (no symptoms) to red (highest symptom score). The heatmap is derived from Figure 2 in Zhou J. et al., Lancet Microbe (2023).
See this image and copyright information in PMC

Update of

  • Lack of association between HLA and asymptomatic SARS-CoV-2 infection.
    Marchal A, Cirulli ET, Neveux I, Bellos E, Thwaites RS, Schiabor Barrett KM, Zhang Y, Nemes-Bokun I, Kalinova M, Catchpole A, Tangye SG, Spaan AN, Lack JB, Ghosn J, Burdet C, Gorochov G, Tubach F, Hausfater P; COVID Human Genetic Effort; COVIDeF Study Group; French COVID Cohort Study Group; CoV-Contact Cohort; COVID-STORM Clinicians; COVID Clinicians; Orchestra Working Group; Amsterdam UMC Covid-19 Biobank; NIAID-USUHS COVID Study Group; Dalgard CL, Zhang SY, Zhang Q, Chiu C, Fellay J, Grzymski JJ, Sancho-Shimizu V, Abel L, Casanova JL, Cobat A, Bolze A. Marchal A, et al. medRxiv [Preprint]. 2023 Dec 8:2023.12.06.23299623. doi: 10.1101/2023.12.06.23299623. medRxiv. 2023. Update in: HGG Adv. 2024 Jul 18;5(3):100300. doi: 10.1016/j.xhgg.2024.100300. PMID: 38168184 Free PMC article. Updated. Preprint.

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