HLA-B*44 and C*01 Prevalence Correlates with Covid19 Spreading across Italy

Abstract

The spread of COVID-19 is showing huge, unexplained, differences between northern and southern Italy. We hypothesized that the regional prevalence of specific class I human leukocyte antigen (HLA) alleles, which shape the anti-viral immune response, might partly underlie these differences. Through an ecological approach, we analyzed whether a set of HLA alleles (A, B, C), known to be involved in the immune response against infections, correlates with COVID-19 incidence. COVID-19 data were provided by the National Civil Protection Department, whereas HLA allele prevalence was retrieved through the Italian Bone-Marrow Donors Registry. Among all the alleles, HLA-A*25, B*08, B*44, B*15:01, B*51, C*01, and C*03 showed a positive log-linear correlation with COVID-19 incidence rate fixed on 9 April 2020 in proximity of the national outbreak peak (Pearson’s coefficients between 0.50 and 0.70, p-value < 0.0001), whereas HLA-B*14, B*18, and B*49 showed an inverse log-linear correlation (Pearson’s coefficients between −0.47 and −0.59, p-value < 0.0001). When alleles were examined simultaneously using a multiple regression model to control for confounding factors, HLA-B*44 and C*01 were still positively and independently associated with COVID-19: a growth rate of 16% (95%CI: 0.1–35%) per 1% point increase in B*44 prevalence; and of 19% (95%CI: 1–41%) per 1% point increase in C*01 prevalence. Our epidemiologic analysis, despite the limits of the ecological approach, is strongly suggestive of a permissive role of HLA-C*01 and B*44 towards SARS-CoV-2 infection, which warrants further investigation in case-control studies. This study opens a new potential avenue for the identification of sub-populations at risk, which could provide Health Services with a tool to define more targeted clinical management strategies and priorities in vaccination campaigns.

Human Leukocyte Antigen Complex and Other Immunogenetic and Clinical Factors Influence Susceptibility or Protection to SARS-CoV-2 Infection and Severity of the Disease Course. The Sardinian Experience

“…According to the results, the prevalence of the HLA-C*01 and HLA-B*44 alleles are predictive of the incidence of COVID-19 in the different Italian regions and therefore confer susceptibility to SARS-CoV-2 infection (34). This association was not observed in the Sardinian population, probably because the HLA-C*01 and HLA-B*44 alleles, while being fairly common in the north eastern areas of Italy, are scarcely represented in the central-south (34). In other populations, the HLA-B*44 allele would seem to exert a protective effect (54), as opposite to what was observed by Correale et al (34).…”

“…This association was not observed in the Sardinian population, probably because the HLA-C*01 and HLA-B*44 alleles, while being fairly common in the north eastern areas of Italy, are scarcely represented in the central-south (34). In other populations, the HLA-B*44 allele would seem to exert a protective effect (54), as opposite to what was observed by Correale et al (34). In our study of the Sardinian population, we found that the HLA-C*04:01 allele conferred susceptibility to SARS-CoV-2 infection.…”

“…It emerged that HLA-A*25, B*08, B*44, B*15:01, B*51, C*01, and C*03 positively correlated with the incidence of SARS-CoV-2 infection, while HLA-B*14, B*18, and B*49 showed an inverse correlation. After applying a multiple regression model to eliminate confounding factors, only the HLA-C*01 and -B*44 alleles, which are present with a higher frequency in the northern regions of Italy, remained positively associated with COVID-19 (34).…”

CD8 T cell epitope generation toward the continually mutating SARS-CoV-2 spike protein in genetically diverse human population: Implications for disease control and prevention

“…In addition to HLA-B � 2705, B44 alleles also had very low number of epitopes (17 for B4402 and 19 for B4403, Table 1). A recent epidemiologic study reported that HLA-B � 44 and HLA-C � 01 positive individuals were more susceptible to SARS-CoV-2 infections in Italy when compared with HLA-A � 25, B � 08, B � 15:01, B � 51, B � 14, B � 18, B � 49, and C � 03 [25]. Although we weren't able to predict the epitopes for C � 01 allele as it hasn't been enlisted in NetMHC 4.0, each of A � 25, B � 08, B � 15:01, B � 51, B � 14, B � 18 and B � 49 alleles we analyzed showed higher numbers of CD8 T cell epitopes than B � 44 (Table 1), indicating broad anti-S protein CD8 T cell responses may provide better protection against SARS-CoV-2 infection.…”

An Effective COVID-19 Vaccine Needs to Engage T Cells

“…Further supporting T cell importance, in silico predictions and epidemiologic studies suggest that COVID-19 vulnerability may depend on the HLA haplotype of a person and its capacity to present SARS-CoV-2 epitopes to T cells. In Italy, prevalence of the potentially permissive alleles HLA-B * 44 and C * 01 correlates with COVID-19 spread (41,42).…”