Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01

January Weiner¹, Phillip Suwalski^{2

3}, Manuel Holtgrewe⁴, Alexander Rakitko⁵, Charlotte Thibeault⁶, Melina Müller², Dimitri Patriki⁷, Claudia Quedenau⁸, Ulrike Krüger⁴, Valery Ilinsky⁵, Iaroslav Popov⁵, Joseph Balnis⁹, Ariel Jaitovich⁹, Elisa T Helbig⁶, Lena J Lippert⁶, Paula Stubbemann⁶, Luis M Real¹⁰, Juan Macías¹⁰, Juan A Pineda¹⁰, Marta Fernandez-Fuertes¹⁰, Xiaomin Wang², Zehra Karadeniz², Jacopo Saccomanno⁶, Jan-Moritz Doehn⁶, Ralf-Harto Hübner⁶, Bernd Hinzmann¹¹, Mauricio Salvo¹¹, Anja Blueher¹¹, Sandra Siemann¹¹, Stjepan Jurisic⁷, Juerg H Beer⁷, Jonas Rutishauser⁷, Benedikt Wiggli⁷, Hansruedi Schmid⁷, Kathrin Danninger¹², Ronald Binder¹², Victor M Corman¹³, Barbara Mühlemann¹³, Rao Arjun Arkal^{14

15

16}, Gabriela K Fragiadakis^{14

15

17}, Eran Mick^{18

19

20}, Consortium Comet²¹, Carolyn S Calfee¹⁸, David J Erle^{14

15

22

18

21

23

24}, Carolyn M Hendrickson¹⁸, Kirsten N Kangelaris²⁴, Matthew F Krummel^{14

16}, Prescott G Woodruff^{14

18

16

25}, Charles R Langelier^{19

20}, Urmila Venkataramani^{14

15}, Federico García²⁶, Joanna Zyla²⁷, Christian Drosten¹³, Braun Alice²⁸, Terry C Jones^{13

29

30}, Norbert Suttorp⁶, Martin Witzenrath⁶, Stefan Hippenstiel⁶, Tomasz Zemojtel⁴, Carsten Skurk², Wolfgang Poller², Tatiana Borodina⁸, Study Group Pa-Covid³¹, Stephan Ripke^{28

32

33}, Leif E Sander⁶, Dieter Beule¹, Ulf Landmesser^{2

34}, Toumy Guettouche¹¹, Florian Kurth⁶, Bettina Heidecker²

Affiliations

¹ Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Unit Bioinformatics Berlin, DE 10178, Germany.
² Department of Cardiology, Charite Universitaetsmedizin Berlin, DE 12203, Germany.
³ Berliner Simulations- und Trainingszentrum, Charite, Berlin, DE 10117, Germany.
⁴ Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Unit Genomics Berlin, DE 10178, Germany.
⁵ Genotek Ltd., Nastavnicheskii pereulok 17/1, R 105120 Moscow, Russian Federation.
⁶ Charite Universitaetsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine Berlin, DE 10117, Germany.
⁷ Kantonsspital Baden AG, Department of Medicine, Baden, CH 5404, Switzerland.
⁸ Max Delbrueck Center for Molecular Medicine Berlin, DE 13125, Germany.
⁹ Department of Molecular and Cellular Physiology, Albany Medical College, NY, USA.
¹⁰ Unidad Clínica de Enfermedades Infecciosas y Microbiología. Hospital Universitario de Valme, Sevilla, ES 41014, Spain.
¹¹ Roche Sequencing Solutions Pleasanton, USA 94588.
¹² Department of Cardiology and Intensive Care, Klinikum Wels-Grieskirchen, Wels, Austria.
¹³ Charite Universitaetsmedizin Berlin, Institute of Virology Chariteplatz, 1 d-10117, Berlin, DE, 10117, Germany.
¹⁴ ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA.
¹⁵ CoLabs, University of California San Francisco, San Francisco, CA, USA.
¹⁶ Department of Pathology, University of California, San Francisco, CA, USA.
¹⁷ Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹⁸ Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California, San Francisco, CA, USA.
¹⁹ Division of Infectious Diseases, University of California, San Francisco, CA, USA.
²⁰ Chan Zuckerberg Biohub, San Francisco, CA, USA.
²¹ COMET (COVID-19 Multiphenotyping for Effective Therapies) Consortium members are listed in the Supplementary Appendix 1.
²² Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
²³ Lung Biology Center, University of California, San Francisco, CA, USA.
²⁴ Department of Medicine, University of California, San Francisco, CA, USA.
²⁵ Sandler Asthma Basic Research Center, University of California, San Francisco, CA, USA.
²⁶ Hospital Universitario Clínico San Cecilio, Instituto de Investigación Ibs. Granada, Spain.
²⁷ Department of Data Science and Engineering, Silesian University of Technology, Gliwice, Poland.
²⁸ Charite Universitaetsmedizin Berlin, Dept. of Psychiatry and Psychotherapy Chariteplatz 1 d-10117 Berlin, DE 10117, Germany.
²⁹ German Center for Infection Research (DZIF), Associated Partner Site, 10117 Berlin, Germany.
³⁰ Centre for Pathogen Evolution, Department of Zoology, University of Cambridge, Downing St., Cambridge, CB2 3EJ, U.K.
³¹ Pa-COVID Study Group, Members are listed in the Supplementary Appendix 2.
³² Massachusetts General Hospital, Analytic and Translational Genetics, Boston, MA 02114, USA.
³³ Stanley Center for Psychiatry Research, Broad Institute of MIT and Harvard Cambridge MA 02142, USA.
³⁴ Berlin Institute of Health at Charité, Berlin, Germany.

PMID: 34490415
PMCID: PMC8410317
DOI: 10.1016/j.eclinm.2021.101099

Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01

January Weiner et al. EClinicalMedicine. 2021 Oct.

. 2021 Oct:40:101099.

doi: 10.1016/j.eclinm.2021.101099. Epub 2021 Sep 2.

Authors

Affiliations

¹ Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Unit Bioinformatics Berlin, DE 10178, Germany.
² Department of Cardiology, Charite Universitaetsmedizin Berlin, DE 12203, Germany.
³ Berliner Simulations- und Trainingszentrum, Charite, Berlin, DE 10117, Germany.
⁴ Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Unit Genomics Berlin, DE 10178, Germany.
⁵ Genotek Ltd., Nastavnicheskii pereulok 17/1, R 105120 Moscow, Russian Federation.
⁶ Charite Universitaetsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine Berlin, DE 10117, Germany.
⁷ Kantonsspital Baden AG, Department of Medicine, Baden, CH 5404, Switzerland.
⁸ Max Delbrueck Center for Molecular Medicine Berlin, DE 13125, Germany.
⁹ Department of Molecular and Cellular Physiology, Albany Medical College, NY, USA.
¹⁰ Unidad Clínica de Enfermedades Infecciosas y Microbiología. Hospital Universitario de Valme, Sevilla, ES 41014, Spain.
¹¹ Roche Sequencing Solutions Pleasanton, USA 94588.
¹² Department of Cardiology and Intensive Care, Klinikum Wels-Grieskirchen, Wels, Austria.
¹³ Charite Universitaetsmedizin Berlin, Institute of Virology Chariteplatz, 1 d-10117, Berlin, DE, 10117, Germany.
¹⁴ ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA.
¹⁵ CoLabs, University of California San Francisco, San Francisco, CA, USA.
¹⁶ Department of Pathology, University of California, San Francisco, CA, USA.
¹⁷ Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹⁸ Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California, San Francisco, CA, USA.
¹⁹ Division of Infectious Diseases, University of California, San Francisco, CA, USA.
²⁰ Chan Zuckerberg Biohub, San Francisco, CA, USA.
²¹ COMET (COVID-19 Multiphenotyping for Effective Therapies) Consortium members are listed in the Supplementary Appendix 1.
²² Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
²³ Lung Biology Center, University of California, San Francisco, CA, USA.
²⁴ Department of Medicine, University of California, San Francisco, CA, USA.
²⁵ Sandler Asthma Basic Research Center, University of California, San Francisco, CA, USA.
²⁶ Hospital Universitario Clínico San Cecilio, Instituto de Investigación Ibs. Granada, Spain.
²⁷ Department of Data Science and Engineering, Silesian University of Technology, Gliwice, Poland.
²⁸ Charite Universitaetsmedizin Berlin, Dept. of Psychiatry and Psychotherapy Chariteplatz 1 d-10117 Berlin, DE 10117, Germany.
²⁹ German Center for Infection Research (DZIF), Associated Partner Site, 10117 Berlin, Germany.
³⁰ Centre for Pathogen Evolution, Department of Zoology, University of Cambridge, Downing St., Cambridge, CB2 3EJ, U.K.
³¹ Pa-COVID Study Group, Members are listed in the Supplementary Appendix 2.
³² Massachusetts General Hospital, Analytic and Translational Genetics, Boston, MA 02114, USA.
³³ Stanley Center for Psychiatry Research, Broad Institute of MIT and Harvard Cambridge MA 02142, USA.
³⁴ Berlin Institute of Health at Charité, Berlin, Germany.

PMID: 34490415
PMCID: PMC8410317
DOI: 10.1016/j.eclinm.2021.101099

Abstract

Background: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing.

Methods: We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany (n = 135), Spain (n = 133), Switzerland (n = 20) and the United States (n = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID-19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS).

Findings: We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted p-value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles.

Interpretation: HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2.

Funding: Funded by Roche Sequencing Solutions, Inc.

Keywords: COVID-19; Genetics; Human Leukocyte Antigen; SARS-CoV-2; intubation.

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Conflict of interest statement

Bettina Heidecker, MD reports support from Roche Sequencing Solutions, Inc; a project grant from the Swiss National Science Foundation; is an inventor on patents that use RNA for diagnosis of myocarditis. Juerg H. Beer, MD reports grants from the Swiss National Foundation of Science, the Swiss Heart Foundation, the Foundation Kardio, Baden; Grant support to the institution from Bayer not related to this study; and lecture fee from Daiichi Sankyo to the institution. Martin Witzenrath, MD reports grants from Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Deutsche Gesellschaft für Pneumologie, European Respiratory Society, Marie Curie Foundation, Else Kröner Fresenius Stiftung, Capnetz Stiftung, International Max Planck Research School, Quark Pharma, Takeda Pharma, Noxxon, Pantherna, Silence Therapeutics, Vaxxilon, Actelion, Bayer Health Care, Biotest, and Boehringer Ingelheim; consulting fees from Noxxon, Pantherna, Silence Therapeutics, Vaxxilon, Aptarion, Glaxo Smith Kline, Sinoxa, and Biotest; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astra Zeneca, Berlin Chemie, Chiesi, Novartis, Teva, Actelion, Boehringer Ingelheim, Glaxo Smith Kline, Biotest, and Bayer Health Care; patent EPO 12,181,535.1: IL-27 for modulation of immune response in acute lung injury issued 2012, patent WO/2010/094,491: Means for inhibiting the expression of Ang-2 issued 2010, and patent DE 102,020,116,249.9: Camostat/ Niclosamide cotreatment in SARS-CoV-2 infected human lung cells issued 2020/21. Alexander Rakitko, Valery Ilinsky, and Iaroslav Popov are employees of Genotek Ltd. Melina Müller declares support for the present manuscript from Roche Sequencing Solutions and Swiss National Science Foundation and Berlin Institutes of Health. Joseph Balnis and Ariel Jaitovich declare support from the National Institute of Health (NIH, K01-HL130704). Bernd Hinzmann, Mauricio A Salvo, Anja Blüher, and Sandra Siemann declare support from Roche Sequencing Solutions. Carolyn Calfee reports NIH payment to her institution; payment from Roche/Genentech Payment and Bayer to her institution for observational study in ARDS; payment from Quantum Leap Healthcare Collaborative to her institution for adaptive platform Phase 2 trial in COVID-19; and consulting fees for novel therapies for ARDS from Vasomune and Quark Pharmaceuticals Payment. David J Erle reports NIH Grants to UCSF. Prescott G Woodruff reports support from Roche Sequencing Solutions, Inc., Swiss National Science Foundation, and Berlin Institutes of Health; US National Institutes of Health grant to his institution (U19AI077439) Charles Langelier reports NIH payment to his institution. Federico García reports grants from ViiV, MSD, and Roche; payment from Abbvie, Gilead, ViiV, MSD, and Roche; support for attending meetings and/or travel from Abbvie and Gilead; participation on a Data Safety Monitoring Board or Advisory Board for Gilead, ViiV, and Thera. Joanna Zyla has been supported by the Silesian University of Technology grant for Support and Development of Research Potential. Terry C. Jones reports a grant from Wellcome Trust, UK, on unrelated research on ancient viral DNA and an NIAID-NIH CEIRS grant (HHSN272201400008C). Leif Erik Sander reports Berlin Institutes of Health support to the PA-COVID-19 study group. Wolfgang Poller reports that this study was partially funded by Roche Sequencing Solutions, Inc., which also provided material for exome sequencing. Ulf Landmesser reports consulting fees from Abbott, Amgen, Bayer, Cardiac Dimensions, Novartis, Pfizer, and Omeicos; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis, Abott, NovoNordisk, Bayer, Amgen, DaiichiSankyo, Pfizer, Sanofi, Boson Scientific, Astra Zeneca, and Boehringer Ingelheim. All other authors have nothing to declare.

Figures

**Fig. 1**
Association between alleles and categorical response parameters in data sets, DS 1–3. Each dot represents one allele / response parameter association. Colors correspond to response parameters in the meta-analysis (intensive care unit, ICU status and intubation status). The Y-axis represents the negative logarithm of the p-value obtained from the logistic regression test. Sizes of dots correspond to the calculated effect size of the associations (log-odds ratios). Dashed vertical line corresponds to the minor allele frequency selection threshold (0.05). Dashed horizontal line corresponds to p-value of 0.05 (not corrected for multiple testing).

**Fig. 2**
Associations of HLA-C*04:01 with intensive care unit (ICU) and intubation status. Each panel shows the difference between patients who were carrying the allele (HLA C*04:01 status: Present) and patients who did not carry the allele (HLA C*04:01 status: Absent). Colors correspond to variable status. The vertical axis shows the absolute number of patients. Data sets, DS 1–3.

**Fig. 3**
a. Meta-analysis on HLA-C*04:01 and COVID-19 severity.b. Meta-analysis on HLA-C*04:01 and COVID-19 susceptibility.Odds ratios (Effect column) for each variant and the corresponding 95% confidence intervals (CI) are plotted as horizontal bars with a square in the middle. The size of the square is proportional to the weight of the corresponding cohort in the meta-analysis. The overall effect for the fixed-effect model is plotted as a diamond and vertical dotted line. For those cohorts where HLA alleles were not studied, we consider rs5010528 as tag SNP for HLA-C*04:01. Effective sample size (Eff. Sample Size) was calculated as 4/(1/N_cases + 1/N_controls). RAF: risk allele frequency.

See this image and copyright information in PMC

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K01 HL130704/HL/NHLBI NIH HHS/United States

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Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01

Affiliations

Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding