AUTHOR=Mocci Stefano , Littera Roberto , Chessa Luchino , Campagna Marcello , Melis Maurizio , Ottelio Carla Maria , Piras Ignazio S. , Lai Sara , Firinu Davide , Tranquilli Stefania , Mascia Alessia , Vacca Monica , Schirru Daniele , Lecca Luigi Isaia , Rassu Stefania , Cannas Federica , Sanna Celeste , Carta Mauro Giovanni , Sedda Francesca , Giuressi Erika , Cipri Selene , Miglianti Michela , Perra Andrea , Giglio Sabrina 

TITLE=A review of the main genetic factors influencing the course of COVID-19 in Sardinia: the role of human leukocyte antigen-G

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1138559

DOI=10.3389/fimmu.2023.1138559

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>A large number of risk and protective factors have been identified during the SARS-CoV-2 pandemic which may influence the outcome of COVID-19. Among these, recent studies have explored the role of HLA-G molecules and their immunomodulatory effects in COVID-19, but there are very few reports exploring the genetic basis of these manifestations. The present study aims to investigate how host genetic factors, including <italic>HLA-G</italic> gene polymorphisms and sHLA-G, can affect SARS-CoV-2 infection.</p></sec><sec><title>Materials and Methods</title><p>We compared the immune-genetic and phenotypic characteristics between COVID-19 patients (n = 381) with varying degrees of severity of the disease and 420 healthy controls from Sardinia (Italy).</p></sec><sec><title>Results</title><p>HLA-G locus analysis showed that the extended haplotype <italic>HLA-G*01:01:01:01/UTR-1</italic> was more prevalent in both COVID-19 patients and controls. In particular, this extended haplotype was more common among patients with mild symptoms than those with severe symptoms [22.7% <italic>vs</italic> 15.7%, OR = 0.634 (95% CI 0.440 – 0.913); P = 0.016]. Furthermore, the most significant <italic>HLA-G 3’UTR</italic> polymorphism (<italic>rs371194629</italic>) shows that the <italic>HLA-G 3’UTR Del/Del</italic> genotype frequency decreases gradually from 27.6% in paucisymptomatic patients to 15.9% in patients with severe symptoms (X<sup>2 </sup>= 7.095, P = 0.029), reaching the lowest frequency (7.0%) in ICU patients (X<sup>2 </sup>= 11.257, P = 0.004). However, no significant differences were observed for the soluble HLA-G levels in patients and controls. Finally, we showed that SARS-CoV-2 infection in the Sardinian population is also influenced by other genetic factors such as β-thalassemia trait (<italic>rs11549407</italic>C&gt;T in the <italic>HBB</italic> gene), <italic>KIR2DS2/HLA</italic>-C C1+ group combination and the <italic>HLA-B*58:01, C*07:01, DRB1*03:01</italic> haplotype which exert a protective effect [P = 0.005, P = 0.001 and P = 0.026 respectively]. Conversely, the Neanderthal <italic>LZTFL1</italic> gene variant (<italic>rs35044562</italic>A&gt;G) shows a detrimental consequence on the disease course [P = 0.001]. However, by using a logistic regression model, <italic>HLA-G 3’UTR Del/Del</italic> genotype was independent from the other significant variables [OR<sub>M</sub> = 0.4 (95% CI 0.2 – 0.7), P<sub>M</sub> = 6.5 x 10<sup>-4</sup>].</p></sec><sec><title>Conclusion</title><p>Our results reveal novel genetic variants which could potentially serve as biomarkers for disease prognosis and treatment, highlighting the importance of considering genetic factors in the management of COVID-19 patients.</p></sec>