Abstract
Background: coronavirus disease 2019 (COVID-19) causes severe illness including cytokine storms, but mortality among countries differs largely. In the present study, we investigated the association between human leukocyte antigen (HLA) class I, which plays a major role in susceptibility to viral infections, and the mortality of COVID-19. Methods: data of allele frequencies of HLA-A, -B and -C and COVID-19 mortality were obtained for 74 countries from the Allele Frequency Net Database and worldometer.info. Association between allele frequency of each HLA and mortality was assessed by linear regression followed by multivariable regression. Subsequently, association of HLA-C*05 to its receptor KIR2DS4fl, expressed on natural killer (NK) cells, and differential mortality to historic pandemics were analyzed. Results: HLA-A*01, -B*07, -B*08, -B*44 and -C*05 were significantly associated with the risk of deaths (adjusted p = 0.040, 0.00081, 0.047, 0.0022, 0.00032, respectively), but only HLA-C*05 remained statistically significant (p = 0.000027) after multivariable regression. A 1% increase in the allele frequency of HLA-C*05 was associated with an increase of 44 deaths/million. Countries with different mortality could be categorized by the distribution of HLA-C*05 and its receptor KIR2DS4fl, which in combination cause NK cell-induced hyperactive immune response. Countries with similar ethnic and/or geographic background responded in a similar pattern to each pandemic. Conclusions: we demonstrated that allele frequency of HLA-C*05 and the distribution pattern with its receptor KIR2DS4fl strongly correlated with COVID-19 mortality. Host genetic variance of innate immunity may contribute to the difference in mortality among various countries and further investigation using patient samples is warranted.
Highlights
The symptoms of coronavirus disease 2019 (COVID-19), which is the acute respiratory syndrome caused by the virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vary from asymptomatic to critically ill [1]
Conclusions: we demonstrated that allele frequency of human leukocyte antigen (HLA)-C*05 and the distribution pattern with its receptor KIR2DS4fl strongly correlated with COVID-19 mortality
We investigated the association between the allele frequency of class I Major histocompatibility complex (MHC) genes, HLA-A, -B and -C, obtained from the Allele Frequency Net Database and the worldwide mortality due to COVID-19
Summary
The symptoms of coronavirus disease 2019 (COVID-19), which is the acute respiratory syndrome caused by the virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vary from asymptomatic to critically ill [1]. It has recently come to attention that the number of infections and deaths among countries worldwide differ largely. In China, where COVID-19 was initially identified, the infection and deaths are 58 and 3 per million population, respectively. Most Asian countries show rates in the range similar to China. In many European countries, these numbers are much greater; e.g., the United Kingdom (UK), Italy and Spain, have rates in the range of 3000–6000 and. The difference in the infection rate can be partly explained by demographic background, healthcare and governmental policies, and approach to diagnostic testing and containment
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