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

Abstract

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, including HLA-G gene 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 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 [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.

Decision trees for early prediction of inadequate immune response to coronavirus infections: a pilot study on COVID-19

“…Typing of the HLA Class I alleles ( HLA-A, HLA-B, HLA-C ), typing of KIR genes, and determination of the 14-bp polymorphism ( Ins/Del ) of the HLA-G gene were performed as described in Mocci et al, Littera et al, Amodio et al, and Caocci et al ( 24–26 , 34 ).…”

“…The aim of the proposed study was to develop an algorithm capable of predicting the risk of developing a more aggressive and severe disease course in individuals before they become infected with SARS-CoV-2. An AI method, combining common demographic risk factors (age and gender) ( 24 , 25 ) with key immunogenetic risk markers, including HLA class I molecule alleles ( HLA-A, -B, -C ) and the 14-base pair polymorphism in the HLA-G gene, is described. In fact, classical and non-classical HLA antigens play a crucial role in activating and regulating innate and adaptive immune responses ( 26 ).…”

Host Genetics and COVID-19: Genes Underlying the Patterns of Susceptibility and Prognosis

“…In this population, it was found that a variant of the LZTFL1 gene (rs35044562A>G) was associated with the unfavorable disease course (p = 0.001). 27 The data on the polymorphisms of eight genes were analyzed for risk of COVID-19 infection and severity: HLA, ABO, angiotensin-converting enzyme 1 (ACE1), angiotensin-converting enzyme 2 (ACE2), apolipoprotein E (ApoE), CCR5, transmembrane protease serine 2 (TMPRSS2), and interferon-induced transmembrane protein 3. The results indicated that variations in the ApoE, ACE, TMPRSS2, CCR5 and HLA genes appeared to be correlated to the susceptibility to and/or severity of COVID-19.…”

HLA-G14-bp variant is associated with exercise-induced oxygen desaturation in the post-COVID-19 condition

“…The 14-bp insertion/deletion (indel) polymorphism, found in the 3′-untranslated region of the HLA-G gene, has been linked to the mRNA stability and the amounts of the sHLA-G plasma levels, with the lowest levels observed in those homozygous for the insertion (Ins) allele (Ins/Ins) [ 7 ]. The indel variant has been controversially associated with COVID-19 susceptibility [ 5 ] and severity [ 8 ]. However, its association with the disease's mortality and post-COVID-19 condition has not been reported.…”