Retrospective<i>in silico</i>HLA predictions from COVID-19 patients reveal alleles associated with disease prognosis

Rm, Warren; Birol, İnanç

doi:10.1101/2020.10.27.20220863

Cited by 26 publications

(43 citation statements)

References 40 publications

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“…Also, after correcting for multiple testing, we did not find significant associations of single allotypes with COVID-19 severity. These results suggest that individual HLA genotypes do not limit the immune response to SARS-CoV-2 infection as presumed by other studies ( 14 – 16 , 36 ). Clinical factors such as age and body mass index had a far greater impact in our population compared to any analyzed factor describing the individual set of HLA molecules ( 34 ).…”

Section: Discussionsupporting

confidence: 71%

Individual HLA-A, -B, -C, and -DRB1 Genotypes Are No Major Factors Which Determine COVID-19 Severity

et al. 2021

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HLA molecules are key restrictive elements to present intracellular antigens at the crossroads of an effective T-cell response against SARS-CoV-2. To determine the impact of the HLA genotype on the severity of SARS-CoV-2 courses, we investigated data from 6,919 infected individuals. HLA-A, -B, and -DRB1 allotypes grouped into HLA supertypes by functional or predicted structural similarities of the peptide-binding grooves did not predict COVID-19 severity. Further, we did not observe a heterozygote advantage or a benefit from HLA diplotypes with more divergent physicochemical peptide-binding properties. Finally, numbers of in silico predicted viral T-cell epitopes did not correlate with the severity of SARS-CoV-2 infections. These findings suggest that the HLA genotype is no major factor determining COVID-19 severity. Moreover, our data suggest that the spike glycoprotein alone may allow for abundant T-cell epitopes to mount robust T-cell responses not limited by the HLA genotype.

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Section: Discussionsupporting

confidence: 71%

Individual HLA-A, -B, -C, and -DRB1 Genotypes Are No Major Factors Which Determine COVID-19 Severity

et al. 2021

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“…On the contrary, we found that only one out of eight HLA-A*02:01 or HLA-A*03:01 homozygous individuals died before 60 years. This fact can be also observed in dataset recently published by Warren with co-authors [35]: none out of five COVID-19 patients homozygous by HLA-A*02:01 or HLA-A*03:01 had severe course of COVID-19 and were admitted to intensive care unit. Thus, presentation of “important” viral peptides with doubled intensity can enhance immune response showing that HLA class I homozygosity can act like a double-edged sword.…”

Section: Discussionsupporting

confidence: 64%

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

Shkurnikov

Nersisyan

Jankevic

et al. 2020

Preprint

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BackgroundHLA 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 FindingsHLA-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.ConclusionsThe 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.

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“…In a preprint article, HLA-A*30:02 was found to be enriched among COVID-19 patients compared with controls without COVID-19, although the association was not statistical significant after adjusting for multiple comparisons. 35 The study appeared to be underpowered with 100 COVID-19 patients and 26 controls, and the descent or ethnicity of the study population was not reported. Our finding of HLA-A*30:02 as a risk factor for COVID-19 among younger African Americans is consistent this earlier report and needs to be confirmed by further studies.…”

Section: Discussionmentioning

confidence: 99%

HLA genetic polymorphism in patients with Coronavirus Disease 2019 in Midwestern United States

Schindler

Dribus

Duffy

et al. 2021

HLA

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The experience of individuals with Coronavirus Disease 2019 (COVID-19) ranges from asymptomatic to life threatening multi-organ dysfunction. Specific HLA alleles may affect the predisposition to severe COVID-19 because of their role in presenting viral peptides to launch the adaptive immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this population-based case-control study in the midwestern United States, we performed high-resolution HLA typing of 234 cases hospitalized for COVID-19 in the St. Louis metropolitan area and compared their HLA allele frequencies with those of 22,000 matched controls from the National Marrow Donor Program (NMDP). We identified two predisposing alleles, HLA-DRB1*08:02 in the Hispanic group (OR = 9.0, 95% confidence interval: 2.2-37.9; adjusted p = 0.03) and HLA-A*30:02 in younger African Americans with ages below the median (OR = 2.2, 1.4-3.6; adjusted p = 0.01), and several candidate alleles with potential associations with COVID-19 in African American, White, and Hispanic groups. We also detected risk-associated amino acid residues in the peptide binding grooves of some of these alleles, suggesting the presence of functional associations. These findings support the notion that specific HLA alleles may be protective or predisposing factors to COVID-19. Future consortium analysis of pooled cases and controls is warranted to validate and extend these findings, and correlation with viral peptide binding studies will provide additional evidence for the functional association between HLA alleles and COVID-19.

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Retrospectivein silicoHLA predictions from COVID-19 patients reveal alleles associated with disease prognosis

Cited by 26 publications

References 40 publications

Individual HLA-A, -B, -C, and -DRB1 Genotypes Are No Major Factors Which Determine COVID-19 Severity

Individual HLA-A, -B, -C, and -DRB1 Genotypes Are No Major Factors Which Determine COVID-19 Severity

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

HLA genetic polymorphism in patients with Coronavirus Disease 2019 in Midwestern United States

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