Innate immunogenetic synergy between KIR and Neanderthal-derived OAS variants predicts COVID-19 outcomes

BACKGROUND: Genetic factors modulate the progression of coronavirus disease 2019 (COVID-19), but interactions between innate immune gene variants remain incompletely understood. Prior work identified Killer Immunoglobulin-like Receptor (KIR) genotypes and Neanderthal-introgressed OAS1/2/3 haplotypes as key modulators of disease severity. Given these parallel findings, we aimed to evaluate the synergistic impact of KIR motifs, Neanderthal-inherited OAS1/2/3 variants, and other immune-related SNPs on COVID-19 symptomatology and severity. METHODS: In a cohort of 175 unvaccinated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive individuals (65 asymptomatic, 47 mild-intermediate, 63 severe), we genotyped KIR/KIR-ligand motifs and variants in OAS1/2/3, IFITM3, DPP4, TLR7, and APOE. Multivariate logistic regression models assessed independent and interactive predictors of symptomatic and severe disease, and ROC curve analysis was performed to quantify their discriminative ability. RESULTS: An interaction between the absence of both the protective tAB1/wL KIR motif and the Neanderthal-derived OAS1/2/3 alleles significantly predicted symptomatic infection (OR 3.47, P = 0.006) and severe disease (OR 2.41, P = 0.038), achieving overall classification accuracies of 75.4% and 78.9%, respectively. Independent predictors included age, male gender, rs12252 (IFITM3) and rs3788979 (DPP4) as risk factors, and blood group A and APOE ε3ε3 status as protective factors. No rare TLR7 variants were detected. CONCLUSION: This study identifies, for the first time, a synergistic interaction between KIR motifs and Neanderthal-derived OAS1/2/3 variants influencing COVID-19 outcomes. These findings highlight the interplay between ancient and modern innate immune adaptations in shaping viral disease susceptibility. Future studies in larger and diverse populations are warranted to validate these immunogenetic interactions.