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

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.

Association of HLA gene polymorphism with susceptibility, severity, and mortality of COVID‐19: A systematic review

“…Relatively fewer alleles of HLA‐C were being explored so far and findings are more or less in agreement. Like C*07:01 was significantly negatively correlated with SARS‐CoV‐2 infection susceptibility and COVID‐related mortality, 17,28 while C*01 and C*04:01 are positively correlated with SARS‐CoV‐2 infection, severity, and mortality 17,23,33,36,42 (Tables 3, 4, and 5).…”

“…Six types of approaches were observed when it came to data sourcing for analysis, including both dry lab and wet lab, which are briefly discussed here—(i) HLA typing for both patient and control group were carried out in wet lab, frequency of different alleles were compared between two groups for any significant differences with different outcomes ( n = 9) 2,14,17,18,25,27,29,31,42 ; (ii) the most frequent HLA alleles were retrieved from AFND for the concerned countries of respected studies, SARS‐CoV‐2 genome was downloaded from NCBI or national databases and peptide binding capacity of frequent alleles was then evaluated using different version of NetMHCpan web server, association of strongly or weakly bound peptides with COVID cases and deaths per million (from worldometer, WHO situation report) were analyzed further through frequency analysis of HLA alleles, as it is established that strongly bound peptide are better presented and weakly bound peptides are poorly presented by MHC to T‐cells and thus can play a major role in adequate immune responses against COVID ( n = 6) 12,13,19–22 ; (iii) HLA allele frequency data for both patient and control group were obtained from national organ donor registry and COVID data from worldometer or national COVID registry, compared allele frequency between healthy and COVID group for identifying any association with COVID susceptibility or among mild, moderate or severe groups of COVID patients to associate HLA with COVID severity and/or mortality ( n = 9) 6,11,28,33,36,38,41,43,44 ; (iv) HLA typing in wet lab was opted for the patient group but reference group were selected from the population with known HLA type through donor registry and after that association with COVID susceptibility, severity or mortality were analyzed ( n = 6) 5,24,26,32,34,45 ; (v) in this approach, metagenomics data from patients were used to predict HLA type using HLA prediction software (HLAminer, OptiType, Seq2HLA, etc.) with or without control group ( n = 4) 1,23,35,40 ; (vi) lastly, two studies observed human monocyte HLA‐DR (mHLA‐DR) expression among healthy people and different clinical stages of COVID patients to identify any impact of altered mHLA‐DR expression with COVID‐19 prognosis ( n = 2) 37,39 (Tables 1 and 2).…”

“…Among 36 studies, seven explored the outcome related to only COVID susceptibility 17,20,22,26,31,35,36 ; 14 studies investigated only severity 1,2,5,18,19,24,27,29,32,37,39,40,42,43 and four studies observed association with only mortality 6,11,13,25 . The association of HLA alleles with either susceptibility and mortality of COVID‐19 12,28,33,34,38 or susceptibility and severity of COVID‐19 14,23,41,44,45 were explored by five studies, respectively and only one study explored HLA association with COVID severity and mortality 21 .…”

“…Just like Figure 3, here also HLAs, for which odds ratios and 95% CI were available with significant p ‐values were considered to provide a visible effect of the range of confidence of the available data for the respective alleles. HLAs that were included in the forest plot is underlined in Table 4 2,17,27,42 …”

Docencia en ginecología y obstetricia en el Perú

“…Se ha descubierto que el estado de portador del HLA-C*04:01 se asocia con una evolución clínica grave del SARS-CoV-2. Es decir, los alelos HLA de clase I tendrían un papel relevante en la defensa inmunitaria contra el SARS-CoV-2 (9) .…”