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

ABSTRACT

During the first and second waves of coronavirus-19 disease, Sardinia had one of the lowest hospitalization and related mortality rates in Europe. However, in contrast with this evidence, the Sardinia population showed a very high frequency of the Neanderthal risk locus variant rs35044562, considered to be a major risk factor for a severe SARS-CoV-2 disease course. We evaluated 358 patients who had tested positive for SARS-CoV-2 and 314 healthy Sardinian controls (Italy). Patients were divided according to WHO classification 120 patients asymptomatic, 90 pauci-symptomatic, 108 with a moderate disease course and 40 severely ill. The allele frequencies of Neanderthal-derived genetic variants reported as being protective (rs1156361) or causative (rs35044562) for severe illness were calculated in patients and controls. The Thalassemia variant (rs11549407), the HLA haplotypes, the KIR genes, as well as KIRs and their HLA class I ligand combinations were also investigated. The rs35044562 and rs1156361 Neanderthal variants revealed a distribution in Hardy-Weinberg equilibrium (HWE) both in SARS-CoV-2 patients and the control population (X2HWE = 0.82, p = 0.37 and X2HWE = 0.13, p = 0.72, respectively). Our findings reported 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<0.0001]. Conversely, the protective effect of the HLA-A*0201~B*1801~DRB1*0301 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.