MHC Haplotyping of SARS-CoV-2 Patients: HLA Subtypes Are Not Associated with the Presence and Severity of COVID-19 in the Israeli Population

Abstract

HLA haplotypes were found to be associated with increased risk for viral infections or disease severity in various diseases, including SARS. Several genetic variants are associated with COVID-19 severity. Studies have proposed associations, based on a very small sample and a large number of tested HLA alleles, but no clear association between HLA and COVID-19 incidence or severity has been reported. We conducted a large-scale HLA analysis of Israeli individuals who tested positive for SARS-CoV-2 infection by PCR. Overall, 72,912 individuals with known HLA haplotypes were included in the study, of whom 6413 (8.8%) were found to have SARS-CoV-2 by PCR. A total of 20,937 subjects were of Ashkenazi origin (at least 2/4 grandparents). One hundred eighty-one patients (2.8% of the infected) were hospitalized due to the disease. None of the 66 most common HLA loci (within the five HLA subgroups: A, B, C, DQB1, DRB1) was found to be associated with SARS-CoV-2 infection or hospitalization in the general Israeli population. Similarly, no association was detected in the Ashkenazi Jewish subset. Moreover, no association was found between heterozygosity in any of the HLA loci and either infection or hospitalization. We conclude that HLA haplotypes are not a major risk/protecting factor among the Israeli population for SARS-CoV-2 infection or severity. Our results suggest that if any HLA association exists with the disease it is very weak, and of limited effect on the pandemic. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-021-01071-x.

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

“…This could be explained, at least partially, by geographical differences and varying population allele frequencies in those cohorts, relatively small cohort sizes (<100 patients), differences in experimentation setup and/or other factors, including comorbidity status, that may be acting independently of HLA. We note that, since the beginning of the COVID-19 pandemic several large-scale studies reported no link between HLA and COVID-19 (COVID-19 Host Genetics Initiative, 2021;Severe Covid-19 GWAS Group et al, 2020;Ben Shachar et al, 2021). It is worth noting that the MHC region of the genome is highly polymorphic and gene-dense, and without a direct measure of HLA, genome wide association studies (GWAS) have limitations when it comes to reporting associations in this region (Kennedy, Ozbek & Dorak, 2017).…”

“…For instance, in the GWAS report from the COVID-19 Host Genetics Initiative (COVID-19 Host Genetics Initiative, 2021), the HLA locus was excluded from their analysis due to the heterogeneity in effect size observed between studies. Yet, in two other separate large-scale reports where HLA was directly measured and with appreciable COVID-19 patient cohort sizes from Italian/Spanish (n > 1,000) and Israeli (n > 72,000) populations, the absence of associations including with disease severity, is noteworthy (Severe Covid-19 GWAS Group et al, 2020;Ben Shachar et al, 2021).…”

“…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).…”

Current HLA Investigations on SARS-CoV-2 and Perspectives

“…Multiple HLA-focused analyses performed during the last 2 years have had greatly varying results with inconsistent associations even in large studies [n = 20,937 in ( Shachar et al, 2021 )]. Further direct HLA allele association studies could provide the necessary power to carefully assess the role of HLA in immune response against SARS-CoV-2, but unfortunately, typing has not been conducted on large samples to date, leading to underpowered studies (most studies with less than 190 individuals).…”

“…More recently, Khor et al (2021) also identified HLA-A*11:01:01:01 as a risk factor for COVID-19 severity ( p -value = 0.003, OR 3.4), in a study involving 190 patients and 423 controls, after controlling for comorbidities and other confounding factors. Shachar et al (2021) showed no association between COVID-19 severity and HLA alleles in a large-scale study of HLA typed Israelis (n = 20,937), though it was limited to two-field information. Finally, Castro de Moura et al investigated the relationship between the epigenome of patients and COVID-19 severity from 407 patients and showed differentially methylated probes in HLA-C associated with the response of interferon in the viral response ( Castro de Moura et al, 2021 ).…”