Association of IL-8 and IL-8R1 gene polymorphisms with COVID-19 mortality

Background Host genetic factors contribute to the heterogeneity of clinical outcomes in Coronavirus Disease 2019 (COVID-19). Interleukin-8 (IL-8) and its receptor IL-8R1 (CXCR1) play key roles in inflammatory responses and cytokine-mediated tissue damage during severe SARS-CoV-2 infection. This study investigated the association of IL-8 rs4073 and rs2227306, as well as IL-8R1 rs2234671 polymorphisms, with COVID-19 mortality in an Iranian population. Methods A total of 328 hospitalized COVID-19 patients, including 178 recovered and 150 deceased individuals, were enrolled. Genotyping of IL-8 rs4073, IL-8 rs2227306, and IL-8R1 rs2234671 polymorphisms was performed using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), and selected samples were confirmed by Sanger sequencing. Genotype and allele frequencies were compared between groups, and logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Multilocus genotype combination analysis was also conducted. Results The IL-8R1 rs2234671 polymorphism showed a significant association with COVID-19 mortality. Carriers of the G allele exhibited an increased risk of death compared with CC homozygotes under codominant, dominant, overdominant, and log-additive inheritance models (all P < 0.05). The strongest association was observed under the dominant model (OR = 3.29, 95% CI = 1.55–6.99, P = 0.0014). In contrast, IL-8 rs4073 and rs2227306 polymorphisms showed no statistically significant associations with mortality when analyzed individually. Multilocus genotype combination analysis suggested that specific combinations involving IL-8R1 rs2234671 may influence clinical outcomes, although these findings require further validation. Conclusions Our findings indicate that the IL-8R1 rs2234671 polymorphism is associated with COVID-19 mortality in the studied Iranian population, supporting the importance of IL-8/CXCR1-mediated inflammatory pathways in disease progression. Although individual IL-8 polymorphisms were not significantly associated with mortality, combined genetic effects may contribute to outcome variability. However, the proposed functional mechanisms remain to be experimentally validated. Larger multi-ethnic studies and functional investigations are needed to validate these associations and clarify their biological significance. Clinical trial number Not applicable.