A Protective HLA Extended Haplotype Outweighs the Major COVID-19 Risk Factor Inherited From Neanderthals in the Sardinian Population

Abstract

Sardinia has one of the lowest incidences of hospitalization and related mortality in Europe and yet a very high frequency of the Neanderthal risk locus variant on chromosome 3 (rs35044562), considered to be a major risk factor for a severe SARS-CoV-2 disease course. We evaluated 358 SARS-CoV-2 patients and 314 healthy Sardinian controls. One hundred and twenty patients were asymptomatic, 90 were pauci-symptomatic, 108 presented a moderate disease course and 40 were severely ill. All patients were analyzed for the Neanderthal-derived genetic variants reported as being protective (rs1156361) or causative (rs35044562) for severe illness. The β°39 C>T Thalassemia variant (rs11549407), HLA haplotypes, KIR genes, KIRs and their HLA class I ligand combinations were also investigated. Our findings revealed an increased risk for severe disease in Sardinian patients carrying the rs35044562 high risk variant [OR 5.32 (95% CI 2.53 - 12.01), p = 0.000]. Conversely, the protective effect of the HLA-A*02:01, B*18:01, DRB*03:01 three-loci extended haplotype in the Sardinian population was shown to efficiently contrast the high risk of a severe and devastating outcome of the infection predicted for carriers of the Neanderthal locus [OR 15.47 (95% CI 5.8 – 41.0), p < 0.0001]. This result suggests that the balance between risk and protective immunogenetic factors plays an important role in the evolution of COVID-19. A better understanding of these mechanisms may well turn out to be the biggest advantage in the race for the development of more efficient drugs and vaccines.

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

“…In previous studies, carried out during the outbreak of the SARS-CoV-2- B.1.1.7 variant in Italy, we observed how specific genetic factors in the Sardinian population significantly impact the outcome of COVID-19 infections ( 36 , 38 , 43 ). We have found that certain genetic factors, including the HLA extended haplotype HLA-B58:01, C07:01, DRB1*03:01, β°39 C>T variant at the HBB gene and KIR2DS2 gene/HLA C1 group ligand combination, can positively influence the course of the disease and result in an asymptomatic outcome ( 36 , 38 , 43 ).…”

“…We have found that certain genetic factors, including the HLA extended haplotype HLA-B58:01, C07:01, DRB1*03:01, β°39 C>T variant at the HBB gene and KIR2DS2 gene/HLA C1 group ligand combination, can positively influence the course of the disease and result in an asymptomatic outcome ( 36 , 38 , 43 ). While the Neanderthal-inherited haplotype ( rs35044562 , rs73064425 , rs34326463 , rs67959919 ) at the leucine zipper transcription factor-like 1 ( LZTFL1 ) has been associated with an increased risk of serious symptoms ( 36 ).…”

“…This allowed us to investigate whether the previously identified risk and protective factors still played a role in the infection caused by this different SARS-CoV-2 variant. Moreover, we explored other genetic traits, such as OAS3 protective haplotype and G6PDH enzyme deficiencies, which have not been found critical in our past studies ( 36 , 38 ).…”

Innate Immunity in Cardiovascular Diseases – Identification of Novel Molecular Players and Targets

“…Two other recent studies illustrate the power of state-of-the-art genetics to reveal fundamentally new insights into immune system evolution [126] and large-scale human evolution in general [127]. Thus, a protective HLA extended haplotype was found to outweigh the major COVID-19 risk factor inherited from Neanderthals in the Sardinian population [126].…”

“…Two other recent studies illustrate the power of state-of-the-art genetics to reveal fundamentally new insights into immune system evolution [126] and large-scale human evolution in general [127]. Thus, a protective HLA extended haplotype was found to outweigh the major COVID-19 risk factor inherited from Neanderthals in the Sardinian population [126]. Another large study [128] conducted multilocus genotyping of SARS-CoV-2 genomes sampled globally and found evidence the majority of SARS-CoV-2 infections in 2020 and 2021 caused by genetically distinct variants that likely adapted to local populations.…”