A rapid ecologic analysis, confirmed by a case–control study, identifies class I HLA alleles correlated to the risk of COVID-19

Background: Several studies suggest that the heterogeneous spread of SARS-CoV-2 pandemics started on December 2019 could be partially upheld by the prevalence of permissive class I HLA alleles in specific populations. Such HLA alleles are in fact unable to shape an efficient anti-viral immune-response in the hosts or sustain an exaggerated inflammatory T cell mediated response responsible for the COVID-19 disease. We previously reported an ecologic correlation between the risk of COVID-19 spreading across Italy and the germinal expression of permissive HLA-C*01 and -B*44 alleles in specific inter and intraregional populations along the first spreading wave. Methods: Considering that SARS-CoV-2 has undergone multiple adaptative mutations since the beginning of pandemics related to a natural immunization and to the worldwide campaign of anti-SARS-CoV-2 vaccination, we have carried out further analyses to evaluate whether the predictive value of class I HLA-allele gene prevalence and COVID-19 incidence has changed with time along the first four pandemics spreading waves in Italy. To this purpose we carried out an ecologic study followed by a case–control study. Results: | Our data revealed that the direct correlation of HLA-C*01, and HLA-B*44 gene expression and COVID-19 risk was completely lost just after the first pandemics wave in Italy. On the contrary, the expression of HLA-B*49 allele in specific populations emerged as inversely correlated to the risk of COVID-19 and could be considered as a protective factor. The statistical significance of this correlation was progressively enforced in each subsequent spreading wave until February 2022. The following case–control study in the two Regions of Campania and Calabria in Italy confirmed the protective value of HLA-B*49 allele gene expression (OR = 0.289; p = 0.041), although statistical significance is lost after adjustment by logistic regression model. The analysis also detected multiple class I HLA-alleles whose expression was strongly correlated with COVID-19 risk: HLA-B*08 (ORadj = 3.193; p = 0.015); -B*14:01 (ORadj = 3.596; p = 0.018); -B*15:01 (ORadj = 5.124; p = 0.001); -B*35 (ORadj = 2.972; p = 0.002). Conclusions: Our study not only identifies specific HLA alleles related to COVID-19 risk but also exemplifies a rapid and inexpensive approach that can be used to identify individuals needing prioritization during vaccination campaigns.