Genetic polymorphisms and expression of SARS-CoV-2 host entry genes associate with COVID-19 severity in an unvaccinated Moroccan cohort

Abstract

Host molecular and genetic factors regulating SARS-CoV-2 entry are increasingly recognized as key determinants of infection susceptibility and disease severity. However, the combined impact of transcriptional and genetic variation in these pathways remains incompletely defined. This study aimed to identify clinically relevant biomarkers associated with COVID-19 outcomes by integrating gene expression and genetic variability analyses of major viral entry factors. We analyzed the expression and genetic variability of key SARS-CoV-2 entry-related genes (ACE2, TMPRSS2, FURIN, and NRP1) in 184 severe patients, 182 benign cases, and 180 healthy controls. Gene expression was quantified by qRT-PCR, and six SNPs (rs2285666, rs2070788, rs1475908, rs4702, rs4932178, rs1412115) were genotyped using TaqMan assays. TMPRSS2 and FURIN were significantly overexpressed in severe COVID-19 patients (p < 0.05) and positively correlated with platelet count (r = 0.34–0.36, p < 0.05). FURIN expression also correlated with viral load (r = 0.40, p = 0.007). Genetically, the TMPRSS2 rs1475908 GG genotype was associated with higher gene expression (p = 0.009), while the A allele conferred protection against disease severity (OR = 0.53, 95% CI: 0.33–0.84, p = 0.006). Conversely, the rs2070788 GA genotype increased infection susceptibility (OR = 1.69, 95% CI: 1.10–2.60, p = 0.048). FURIN rs4702 was significantly associated with both infection risk and severe disease (OR = 1.53, p = 0.002; OR = 1.60, p = 0.012). After FDR correction, the association of rs4702 with infection susceptibility remained statistically significant. Haplotype analyses further supported these findings, highlighting the role of TMPRSS2 in disease severity and FURIN in susceptibility. Our findings identify TMPRSS2 and FURIN as biomarkers that integrate transcriptional and genetic signatures. These variants, particularly FURIN rs4702 and TMPRSS2 rs1475908, may hold potential utility for early risk stratification and personalized management of COVID-19.