HLA-C^*04:01 is a Genetic Risk Allele for Severe Course of COVID-19

Abstract

BackgroundSince 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.MethodsWe 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).ResultsWe 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.ConclusionsHLA-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.

HLA alleles measured from COVID-19 patient transcriptomes reveal associations with disease prognosis in a New York cohort

“…Interestingly, the latter HLA class II allele was also found associated with less severe symptoms in a regional cohort from the North of England (Langton et al, 2021). In a study from Germany, Weiner and co-workers (Weiner et al, 2020) HLA typed 233 COVID-19 patients from Germany, Spain, and Switzerland and found HLA-I C*04:01 to be associated with an increased risk of intubation in COVID-19 patients, consistent with our findings. In their preprint, they also present a validation of their observations, using the Overmyer (Overmyer et al, 2020) cohort data analyzed herein.…”

“…Since we first reported on our observations (Warren & Birol, 2020b), a few additional notable HLA association with COVID-19 reports became available (Khor et al, 2021;Weiner et al, 2020;Langton et al, 2021;Augusto et al, 2021). Of interest, mining the US marrow donor program data bank, Augusto and co-workers uncovered an association between HLA-B*15:01 and asymptomatic SARS-CoV-2 infections (Augusto et al, 2021), which is stronger when haplotyped with HLA-DRB1*04:01.…”

“…Since the beginning of the pandemic, worldwide reports have emerged on host susceptibility to COVID-19 (Ovsyannikova et al, 2020;COVID-19 Host Genetics Initiative, 2021), including reports of possible associations with HLA (Correale et al, 2020;Novelli et al, 2020;Pisanti et al, 2020;Poulton et al, 2020;Khor et al, 2021;Wang et al, 2019;Warren & Birol, 2020a;Weiner et al, 2020;Langton et al, 2021;Augusto et al, 2021) and reports with absence of a definite link in certain populations (Severe Covid-19 GWAS Group et al, 2020;Ben Shachar et al, 2021). Using publicly available metatranscriptomic sequencing data made available at the pandemic onset, we had demonstrated the utility of a high throughput in silico method for characterizing the HLA types of COVID-19 patients from bronchoalveolar lavage fluid and blood samples and reported on prevalent alleles, including the DPA1*02:02P -DPB1*05:01P HLA-II haplotype observed in seven out of eight of patients from two small cohorts (Warren & Birol, 2020a).…”

High‐resolution HLA genotyping identifies alleles associated with severe COVID‐19: A preliminary study from India

“…We report the risk associated with HLA‐C*04:01:01:01 and development of symptoms in COVID‐19 patients and also confirm earlier findings from a multi‐ethnic group (Germany, Spain, Switzerland, and the United States) that identified an enhanced risk of requirement for intubation in COVID‐19 patients. 5 …”

“…We report the risk associated with HLA-C*04:01:01:01 and development of symptoms in COVID-19 patients and also confirm earlier findings from a multi-ethnic group (Germany, Spain, Switzerland, and the United States) that identified an enhanced risk of requirement for intubation in COVID-19 patients. 5 Global distribution frequency for the other alleles at the 4-field level of resolution could not be retrieved. DRB5*01:01:01:02 is a recently identified allele in a Chinese individual and differs from DRB5*01:01:01 by changes in the intron 2 at four positions.…”