Genetic variations in AAK1 and ADAM17 associated with circulatory cytokines changes influence COVID-19 susceptibility and severity

Background: The interplay between genetic factors and COVID-19 susceptibility and severity underscores the critical roles of genetic variations in the responses to the virus. Specifically, genetic variations in genes such as AAK1 and ADAM17 may influence the molecular pathways that determine how the virus enters cells and how the immune system responds, thereby affecting disease outcomes. Identifying these potential genetic variants clarifies individual responses to infectious diseases and helps aid in developing effective targeted therapeutic strategies. Methods: We performed targeted next-generation sequencing focusing on specific single-nucleotide variants (SNVs) in AAK1, ADAM17, and CD209 genes, which are implicated in the entry of SARS-CoV-2 into host cells. The study was conducted in a Middle Eastern cohort, comprising 96 COVID-19 patients with varying disease severities and 69 healthy controls. The correlation between the prevalence of the investigated genetic variants and the serum level of inflammatory cytokines within the studied cohort was also evaluated. Results: Our analysis revealed statistically significant differences in genetic variants between COVID-19 patients and healthy controls. Notably, a 5’UTR variant, rs12692386: chr2:9695906, A > G, in the ADAM17 gene showed a significant association (p = 0.039). Additionally, two variants in the AAK1 gene, an intronic variant chr2:69732672, C > A (p = 0.029) and a missense variant rs1275698668: chr2:69747984, G > C (p = 0.017), were identified, suggesting their potential role in influencing disease susceptibility and severity. The gender-stratified analysis between the two groups showed a significant difference in the AAK1-SNV-rs1275698668 (p = 0.027) in female susceptibility, suggesting a protective effect against SARS-CoV-2 infection. The AAK1-SNV-rs1275698668 showed a significant difference between the three severity groups (p = 0.045). Prediction in-silico tools suggest that 2:g.69747984G > C and 2:g.9,695,906 A > G have potential functional/regulatory impacts on the ADAM17 and AAK1 genes, respectively. Moreover, different correlation patterns between the identified genetic variants and inflammatory cytokine levels (including CD40 ligand, IL-1b, GM-CSF, and IL-4) were observed in COVID-19 patients. Conclusions: Our findings suggest potential genetic biomarkers in AAK1 and ADAM17 genes that could affect the disease severity and circulating cytokine levels in COVID-19 patients.