IntroductionA 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, includingHLA-Ggene polymorphisms and sHLA-G, can affect SARS-CoV-2 infection.Materials and MethodsWe 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).ResultsHLA-G locus analysis showed that the extended haplotypeHLA-G*01:01:01:01/UTR-1was 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%vs15.7%, OR = 0.634 (95% CI 0.440 – 0.913); P = 0.016]. Furthermore, the most significantHLA-G 3’UTRpolymorphism (rs371194629) shows that theHLA-G 3’UTR Del/Delgenotype frequency decreases gradually from 27.6% in paucisymptomatic patients to 15.9% in patients with severe symptoms (X2= 7.095, P = 0.029), reaching the lowest frequency (7.0%) in ICU patients (X2= 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 (rs11549407C>T in theHBBgene),KIR2DS2/HLA-C C1+ group combination and theHLA-B*58:01, C*07:01, DRB1*03:01haplotype which exert a protective effect [P = 0.005, P = 0.001 and P = 0.026 respectively]. Conversely, the NeanderthalLZTFL1gene variant (rs35044562A>G) shows a detrimental consequence on the disease course [P = 0.001]. However, by using a logistic regression model,HLA-G 3’UTR Del/Delgenotype was independent from the other significant variables [ORM= 0.4 (95% CI 0.2 – 0.7), PM= 6.5 x 10-4].ConclusionOur 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.