HLA-C* 04:01 Is A Genetic Risk Allele For Severe Course Of COVID-19

ABSTRACT

Background Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing demand to identify predictors of 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. We sought to evaluate this hypothesis by conducting an international multicenter study using HLA sequencing with subsequent independent validation.

Methods We analyzed a total of 332 samples. First, we enrolled 233 patients in Germany, Spain, and Switzerland for HLA and whole exome sequencing. Furthermore, we validated our results in a public data set (United States, n=99). Patients older than 18 years presenting with COVID-19 were included, representing the full spectrum of the disease. HLA candidate alleles were identified in the derivation cohort (n=92) and tested in two independent validation cohorts (n=240).

Results We identified HLA-C* 04:01 as a novel genetic predictor for severe clinical course in COVID-19. Carriers of HLA-C* 04:01 had twice the risk of intubation when infected with SARS-CoV-2 (hazard ratio 2.1, adjusted p-value=0.0036). Importantly, these findings were successfully replicated in an independent data set. Furthermore, our findings are biologically plausible, as HLA-C* 04:01 has fewer predicted bindings sites with relevant SARS-CoV-2 peptides as compared to other HLA alleles. Exome sequencing confirmed findings from HLA analysis.

Conclusions HLA-C* 04:01 carriage is associated with a twofold increased risk of intubation in patients infected with SARS-CoV-2. Testing for HLA-C* 04:01 could have clinical implications to identify high-risk patients and individualize management.

Competing Interest Statement

This study was partially funded by Roche Sequencing Solutions, Inc., which also provided material for exome sequencing. Bettina Heidecker, MD is an inventor on patents that use RNA for diagnosis of myocarditis. Juerg H. Beer, MD has received grant support from the Swiss National Science Foundation and of the Swiss Heart Foundation. Martin Witzenrath, MD is supported by grants from the German Research Foundation, SFB-TR84 C6 and C9, SFB 1449 B2, by the German Ministry of Education and Research (BMBF) in the framework of the CAPSyS (01ZX1304B), CAPSyS-COVID (01ZX1604B), SYMPATH (01ZX1906A), PROVID (01KI20160A) P4C (16GW0141), MAPVAP (16GW0247), NUM-NAPKON (01KX2021), and by the Berlin Institute of Health (CM-COVID). Martin Witzenrath, MD received research funding from the Deutsche Forschungsgemeinschaft, Bundesministerium fuer Bildung und Forschung, Deutsche Gesellschaft fuer Pneumologie, European Respiratory Society, Marie Curie Foundation, Else Kroener Fresenius Stiftung, Capnetz Stiftung, International Max Planck Research School, Actelion, Bayer Health Care, Biotest, Boehringer Ingelheim, Noxxon, Pantherna, Quark Pharma, Silence Therapeutics, Takeda Pharma, Vaxxilon, sowie fuer Vortraege oder Beratertaetigkeit von Actelion, Aptarion, Astra Zeneca, Bayer Health Care, Berlin Chemie, Biotest, Boehringer Ingelheim, Chiesi, Glaxo Smith Kline, Novartis, Noxxon, Pantherna, Silence Therapeutics, Sinoxa, Teva und Vaxxilon.

Clinical Trial

German and WHO international clinical trials registry, DRKS00021688

Funding Statement

This work was supported through research funding from Roche Sequencing Solutions, Inc. and a project grant from the Swiss National Science Foundation issued to Bettina Heidecker, MD (Money Follows Researcher Program). This work was supported by the Berlin Institutes of Health (B.I.H. support to the PA-COVID-19 study group, represented by L.E.S and M.W.).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the ethics committee of Charite Universitaetsmedizin Berlin, Germany (EA2/066/20), the Ethikkommission Nordwest- und Zentralschweiz, Basel, Switzerland (2020-00952), and the Ethics Committee of the Hospital Universitario de Valme, Sevilla Spain (1346-N-16).

All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

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Yes

Footnotes

• Pa-COVID-19 Study Group: Mirja Mittermaier;Tilman Lingscheid; Pinkus Tober-Lau; Lil Meyer- Arndt; Sascha S.Haenel; Laure Bosquillon de Jarcy; Moritz Pfeiffer; Miriam S. Stegemann; Robert Roehle; Janine Wiebach; Thomas Zoller; Holger Müller-Redetzky; Alexander Uhrig; Felix Balzer; Christof von Kalle; Sascha Treskatsch; Stefan Angermair; Julia Heeschen; Linda Jürgens; Malte Kleinschmidt; Sophy Denker; Christoph Ruwwe-Glösenkamp; Bettina Temmesfeld-Wollbrück; Katrin M. Heim; Dirk Schürmann; Andreas Hocke; Bastian Opitz; Belén Millet Pascual-Leone; Rosa C. Schuhmacher; Nadine Olk; David Hillus; Felix Machleidt; Sebastian Albus; Felix Bremer; Carmen Garcia; Philipp Knape; Philipp M; Krause, Liron Lechtenberg; Yaosi Li; Panagiotis Pergantis; Teresa Ritter; Berna Yedikat; Christian Zobel; Friederike L. Hefele; Ute Kellermann; Mariana Schürmann; Lisa-Marie Wackernagel; Anne Wetzel; Daniel Grund; Jens K. Haumesser; Johannes Hodes; Johannes Rein; Peter Radünzel; Astrid Breitbart; Sergej Münzenberg; Dominik Soll; Tamar Zhamurashvili; Florian Alius; Tim Andermann; Thomas Cronen; Simon Fraumann; Nikolaj Frost; Dominik Geus; Gisele J. Godzick- Njomgang; Anne Herholz; Vera Hermanns; Moritz Hilbrandt; Till Jacobi; Ye-Ji Kim; Elena Madlung; Luise Martin; Nikolai Menner; Agata Mikolajewska; Luisa Mrziglod; Nadine Muller; Michaela Niebank; Eva Pappe; Frieder Pfäfflin; Lennart Pfannkuch; Matthias Raspe; Nicola Reck; Anne Ritter; Laura K. Schmalbrock; Fridolin Steinbeis; Christoph Tabeling; Markus Vogtmann; Susanne Weber; Markus Brack; Matthias Felten; Sein Schmidt; Maria Rönnefarth; Georg Schwanitz; Alexander Krannich; Saskia Zvorc; Uwe D. Behrens; Lucie Kretzler; Linna Li; Isabelle Wirsching; Chantip Dang-Heine; Michael Hummel; Dana Briesemeister; Denise Treue, Martin Möckel; Samuel Knauß; Matthias Endres; Claudia Spies; Steffen Weber; Carstens, Jan M. Kruse; Daniel Zickler; Andreas Edel; Britta Stier; Philipp Enghard; Roland Körner; Kai-Uwe Eckardt; Lucas Elbert; Christopher Neumann; Marius A. Eckart; Thuy N. Pham; Solveig Schönberger; Alexander Wree; Frank Tacke; Josef Mang; Nadia A. de Vries; Marcel Wittenberg, Jana Riecke

Data Availability

For data privacy reasons, the raw data cannot be made available.