Association of HLA class I genotypes with age at death of COVID-19 patients

Background HLA class I molecules play a crucial role in the development of a specific immune response to viral infections by presenting viral peptides to cell surface where they will be further recognized by T cells. In the present manuscript we explored whether HLA class I genotype can be associated with critical course of COVID-19 by searching possible connections between genotypes of deceased patients and their age at death. Methods and Findings HLA-A, HLA-B and HLA-C genotypes of n = 111 deceased patients with COVID-19 (Moscow, Russia) and n = 428 volunteers were identified with targeted next-generation sequencing. Deceased patients were splitted into two groups according to age at death: n = 26 adult patients with age at death below 60 completed years (inclusively) and n = 85 elderly patients over 60. With the use of HLA class I genotypes we developed a risk score which is associated with the ability to present SARS-CoV-2 peptides by an individual’s HLA class I molecule set. The resulting risk score was significantly higher in the group of deceased adults compared to elderly adults ( p = 0.00348, AUC ROC = 0.68). In particular, presence of HLA-A*01:01 allele was associated with high risk, while HLA-A*02:01 and HLA-A*03:01 mainly contributed to the low risk group. The analysis of homozygous patients highlighted the results even stronger: homozygosity by HLA-A*01:01 mainly accompanied early deaths, while only one HLA-A*02:01 homozygote died before 60. Conclusions The obtained results suggest the important role of HLA class I peptide presentation in the development of a specific immune response to COVID-19. While prediction of age at death by HLA class I genotype had a reliable performance, involvement of HLA class II genotype can make it even higher in the future studies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Ministry of Science and Higher Education of the Russian Federation allocated to the Center for Precision Genome Editing and Genetic Technologies for Biomedicine of the Pirogov Russian National Research Medical University, grant No. 075-15-2019-1789 (T.J., I.G., V.V); Russian Foundation for Basic Research (RFBR), project number 20-04-60399 (A.T.); Basic Research Program at HSE University funded by the Russian Academic Excellence Project '5-100' (M.S., S.N., A.G.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### 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: The study protocol was reviewed and approved by the Local Ethics Committee at the Pirogov Russian National Research Medical University (Meeting No. 194 of March 16 2020, Protocol No. 2020/07); the study was conducted in accordance with the Declaration of Helsinki. 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 I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All relevant data are within the manuscript and its Supporting Information files.