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

Abstract

Introduction: 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 HLA-G gene polymorphisms and sHLA-G, can affect SARS-CoV-2 infection.

Materials and methods: 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).

Results: HLA-G locus analysis showed that the extended haplotype HLA-G*01:01:01:01/UTR-1 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% vs 15.7%, OR = 0.634 (95% CI 0.440 - 0.913); P = 0.016]. Furthermore, the most significant HLA-G 3'UTR polymorphism (rs371194629) shows that the HLA-G 3'UTR Del/Del genotype 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 the HBB gene), KIR2DS2/HLA-C C1+ group combination and the HLA-B*58:01, C*07:01, DRB1*03:01 haplotype which exert a protective effect [P = 0.005, P = 0.001 and P = 0.026 respectively]. Conversely, the Neanderthal LZTFL1 gene 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/Del genotype was independent from the other significant variables [OR_M = 0.4 (95% CI 0.2 - 0.7), P_M = 6.5 x 10^-4].

Conclusion: 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.

Keywords: COVID-19; HLA-G 3’UTR haplotypes; KIR2DS2 gene; Sardinian population; neanderthal LZTFL1 variants; soluble HLA-G.

Figure 1

Graphical representation of HLA-G 3’UTR 14bp Ins/Del allele frequency (A), HLA-G 3’UTR 14bp Del/Del genotype frequency (B), HLA-G 3’UTR 14bp Ins/Ins genotype frequency (C) and HLA-G 3’UTR 14bp Ins/Del genotype frequency. Data extracted from controls, Group A (Paucisymptomatic patients), Group S (patients with severe symptoms) and ICU (critical patients admitted in Intensive Care Unit). P values were calculated by using the two-tailed Fisher’s exact test. Only P values less than 0.05 are reported in the figure corresponding to significant differences between the frequencies of the HLA-G 3’UTR 14-bp polymorphism (Ins or Del) and the HLA-G genotype (Del/Del or Ins/Ins and Ins/Del) in the control sample and in the groups of patients. Table S5 in the Supplementary Material reports the P values for all the possible comparisons between the HLA-G polymorphism and genotypes in the groups of controls and patients. *To calculate the P values between Group S and ICU, we excluded the patients in ICU from Group S.