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[Preprint]. 2023 Dec 8:2023.12.06.23299623.

doi: 10.1101/2023.12.06.23299623.

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

Astrid Marchal^{1

2}, Elizabeth T Cirulli³, Iva Neveux⁴, Evangelos Bellos⁵, Ryan S Thwaites⁶, Kelly M Schiabor Barrett³, Yu Zhang⁷, Ivana Nemes-Bokun⁵, Mariya Kalinova⁸, Andrew Catchpole⁸, Stuart G Tangye^{9

10}, András N Spaan^{11

12}, Justin B Lack¹³, Jade Ghosn^{14

15}, Charles Burdet^{14

16

17}, Guy Gorochov¹⁸, Florence Tubach¹⁹, Pierre Hausfater^{20

21}; 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; Clifton L Dalgard²², Shen-Ying Zhang^{1

2

11}, Qian Zhang^{1

2

11}, Christopher Chiu⁵, Jacques Fellay^{23

24

25}, Joseph J Grzymski^{4

26}, Vanessa Sancho-Shimizu^{5

27}, Laurent Abel^{1

2

11}, Jean-Laurent Casanova^{1

2

11

28}, Aurélie Cobat^{1

2

11}, Alexandre Bolze³

Affiliations

¹ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France, EU.
² University Paris Cité, Imagine Institute, Paris, France, EU.
³ Helix, San Mateo, CA, USA.
⁴ Department of Internal Medicine, University of Nevada School of Medicine, Reno, NV, USA.
⁵ Department of Infectious Diseases, Imperial College London, London, United Kingdom.
⁶ National Heart and Lung Institute, Imperial College London, London, United Kingdom.
⁷ Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, Bethesda, MD, USA.
⁸ hVIVO Services Ltd., London, UK.
⁹ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
¹⁰ St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia.
¹¹ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
¹² Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands, EU.
¹³ NIAID Collaborative Bioinformatics Resource, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD, USA.
¹⁴ Infection, Antimicrobials, Modelling, Evolution (IAME), INSERM, UMR1137, University of Paris, Paris, France, EU.
¹⁵ AP-HP, Bichat Claude Bernard Hospital, Infectious and Tropical Diseases Department, Paris, France, EU.
¹⁶ Epidémiologie clinique du Centre d'Investigation Clinique (CIC-EP), INSERM CIC 1425, Hôpital Bichat, 75018 Paris, France, EU.
¹⁷ Département Epidémiologie, Biostatistiques et Recherche Clinique, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, 75018 Paris, France, EU.
¹⁸ Sorbonne Université, INSERM Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Département d'immunologie Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France, EU.
¹⁹ Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpital Pitié Salpêtrière, Département de Santé Publique, Unité de Recherche Clinique PSL-CFX, CIC-1901, Paris, France, EU.
²⁰ Emergency Department, Hôpital Pitié-Salpêtrière, APHP-Sorbonne Université, Paris, France, EU.
²¹ GRC-14 BIOFAST Sorbonne Université, UMR INSERM 1135, CIMI, Sorbonne Université, Paris, France, EU.
²² Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
²³ School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
²⁴ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
²⁵ Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
²⁶ Renown Health, Reno, NV, USA.
²⁷ Centre for Paediatrics and Child Health, Faculty of Medicine, Imperial College London, London, UK.
²⁸ Howard Hughes Medical Institute, New York, NY, USA.

PMID: 38168184
PMCID: PMC10760282
DOI: 10.1101/2023.12.06.23299623

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

Astrid Marchal et al. medRxiv. 2023.

[Preprint]. 2023 Dec 8:2023.12.06.23299623.

doi: 10.1101/2023.12.06.23299623.

Authors

Affiliations

¹ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France, EU.
² University Paris Cité, Imagine Institute, Paris, France, EU.
³ Helix, San Mateo, CA, USA.
⁴ Department of Internal Medicine, University of Nevada School of Medicine, Reno, NV, USA.
⁵ Department of Infectious Diseases, Imperial College London, London, United Kingdom.
⁶ National Heart and Lung Institute, Imperial College London, London, United Kingdom.
⁷ Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, Bethesda, MD, USA.
⁸ hVIVO Services Ltd., London, UK.
⁹ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
¹⁰ St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia.
¹¹ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
¹² Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands, EU.
¹³ NIAID Collaborative Bioinformatics Resource, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD, USA.
¹⁴ Infection, Antimicrobials, Modelling, Evolution (IAME), INSERM, UMR1137, University of Paris, Paris, France, EU.
¹⁵ AP-HP, Bichat Claude Bernard Hospital, Infectious and Tropical Diseases Department, Paris, France, EU.
¹⁶ Epidémiologie clinique du Centre d'Investigation Clinique (CIC-EP), INSERM CIC 1425, Hôpital Bichat, 75018 Paris, France, EU.
¹⁷ Département Epidémiologie, Biostatistiques et Recherche Clinique, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, 75018 Paris, France, EU.
¹⁸ Sorbonne Université, INSERM Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Département d'immunologie Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France, EU.
¹⁹ Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpital Pitié Salpêtrière, Département de Santé Publique, Unité de Recherche Clinique PSL-CFX, CIC-1901, Paris, France, EU.
²⁰ Emergency Department, Hôpital Pitié-Salpêtrière, APHP-Sorbonne Université, Paris, France, EU.
²¹ GRC-14 BIOFAST Sorbonne Université, UMR INSERM 1135, CIMI, Sorbonne Université, Paris, France, EU.
²² Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
²³ School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
²⁴ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
²⁵ Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
²⁶ Renown Health, Reno, NV, USA.
²⁷ Centre for Paediatrics and Child Health, Faculty of Medicine, Imperial College London, London, UK.
²⁸ Howard Hughes Medical Institute, New York, NY, USA.

PMID: 38168184
PMCID: PMC10760282
DOI: 10.1101/2023.12.06.23299623

Update in

Lack of association between classical HLA genes 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. HGG Adv. 2024 Jul 18;5(3):100300. doi: 10.1016/j.xhgg.2024.100300. Epub 2024 Apr 26. HGG Adv. 2024. PMID: 38678364 Free PMC article.

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 US (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, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified. These findings suggest that memory T-cell immunity to seasonal coronaviruses does not strongly influence the outcome of SARS-CoV-2 infection in unvaccinated individuals.

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Figures

**Figure 1:. Study design.**
A: Description of the two cohorts and definitions of asymptomatic and symptomatic cases. B: List of HLA-wide association studies and meta-analyses performed.

**Figure 2:. HLA-B*15:01 is not enriched in asymptomatic cases.**
A: Odds Ratio (OR) and 95% confidence intervals (CI) for the association of HLA-B*15:01 with asymptomatic SARS-CoV-2 infection in both cohorts and in the meta-analysis. B: Allele frequency and 95% confidence intervals in the US prospective cohort subgroups.
C: Allele frequency and 95% CI in the CHGE European sample.
D: Allele frequency and 95% CI in individuals highly exposed to SARS-CoV-2 who never tested positive (‘Resistors’, n=291) and children with SARS-CoV-2 infection complicated by multisystem inflammatory syndrome (‘MIS-C’, n=235) from the European CHGE sample. E: Allele frequency and 95% CI in Middle Eastern (ME) individuals from the CHGE cohort (Symptomatic, n=895; Asymptomatic, n=37).

**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

References

1. Asano T., Boisson B., Onodi F., Matuozzo D., Moncada-Velez M., Maglorius Renkilaraj M.R.L., Zhang P., Meertens L., Bolze A., Materna M., et al. (2021). X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19. Sci Immunol 6,. - PMC - PubMed
1. Kousathanas A., Pairo-Castineira E., Rawlik K., Stuckey A., Odhams C.A., Walker S., Russell C.D., Malinauskas T., Wu Y., Millar J., et al. (2022). Whole-genome sequencing reveals host factors underlying critical COVID-19. Nature 607, 97–103. - PMC - PubMed
1. COVID-19 Host Genetics Initiative (2021). Mapping the human genetic architecture of COVID-19. Nature 600, 472–477. - PMC - PubMed
1. Redin C., Thorball C.W., and Fellay J. (2022). Host genomics of SARS-CoV-2 infection. Eur. J. Hum. Genet. 30, 908–914. - PMC - PubMed
1. Cobat A., Zhang Q., Covid Human Genetic Effort, Abel L., Casanova J.-L., and Fellay J. (2023). Human Genomics of COVID-19 Pneumonia: Contributions of Rare and Common Variants. Annu Rev Biomed Data Sci. - PMC - PubMed

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This is a preprint.

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

Affiliations

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

Authors

Affiliations

Update in

Abstract

Figures

References

Publication types

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous