Genetic, Sociodemographic and Clinical Determinants of COVID-19 Severity in the Republic of Srpska: Exploring Potential Links with Neanderthal-Derived Variants

<b>Background/Objectives:</b> COVID-19 severity is influenced by a complex interplay between host, viral, and environmental factors. Emerging evidence suggests that Neanderthal-derived genetic variants may influence the progression and severity of SARS-CoV-2 infection. This study aimed to evaluate the association between selected Neanderthal-derived variants and COVID-19 severity in the population of the Republic of Srpska, considering relevant clinical, sociodemographic, and lifestyle factors. <b>Methods:</b> This multicentric cross-sectional study included 402 participants, classified as healthy or SARS-CoV-2-positive individuals. A total of 378 COVID-19-positive participants were further stratified according to disease severity and hospitalization status. All individuals were genotyped for the Neanderthal-derived <i>OAS3</i> rs1156361 (C/T) and <i>LZTFL1</i> rs35044562 (A/G) variants. Detailed sociodemographic, clinical, and lifestyle data were also collected. <b>Results:</b> A higher frequency of the <i>LZTFL1</i> rs35044562 AG genotype was observed among hospitalized patients compared with non-hospitalized individuals (36.8% vs. 20.9%; <i>p</i> = 0.005), while the AA genotype was more prevalent among non-hospitalized patients (77.3% vs. 63.2%, <i>p</i> = 0.015). Multivariable logistic analysis showed that carriers of the <i>LZTFL1</i> AG genotype had a higher chance of hospitalization compared to AA carriers (adjusted OR = 1.372, 95% CI = 0.763-6.383, and <i>p</i> = 0.021). Hospitalized patients more frequently carried the combined CT (<i>OAS3</i>) and AG (<i>LZTFL1</i>) genotypes, supporting a potential synergistic effect. Several sociodemographic factors, including age, sex, education, employment, and urban residence, were also associated with COVID-19 severity, while no significant associations were observed in allele-based analyses. <b>Conclusions:</b><i>LZTFL1</i> gene polymorphisms may influence COVID-19 severity, with heterozygote-specific and combined risk effects observed. These preliminary findings are exploratory and require validation in larger cohorts, but may guide future studies and targeted interventions in high-risk groups.