Genetic factors associated with COVID-19 severity and mortality: TYK2 and NOTCH4

The clinical manifestations and outcomes of coronavirus disease (COVID-19) vary among patients. Emerging evidence indicates that host genetic factors may influence disease severity. Genome-wide association studies (GWAS) have identified several genetic loci, including TYK2 and NOTCH4, as contributors to COVID-19 pathogenesis. The present study examined the association between genetic variants of TYK2 (rs74956615) and NOTCH4 (rs3131294) and the severity and mortality of COVID-19 in a Jordanian cohort. The present study included 362 patients with COVID-19 who were admitted to a hospital in Amman, Jordan. Clinical severity was categorized according to the WHO guidelines (non-severe, severe and critical), and outcomes were classified as survivors or non-survivors. Blood samples were collected, and DNA was extracted. Genotyping of TYK2 and NOTCH4 single-nucleotide polymorphisms was performed using PCR and Sanger sequencing. The frequencies of heterozygous and variant alleles of TYK2 and NOTCH4 were significantly higher in patients with critical disease than in non-survivors (P<0.001). Logistic regression analysis revealed that individuals with heterozygous or variant alleles of NOTCH4 had 15.3 times higher odds of developing severe/critical conditions (P=0.010), while those with variant alleles of TYK2 and NOTCH4 had approximately eight times higher odds of mortality (P<0.001 for both). TYK2 and NOTCH4 variants are markedly associated with increased COVID-19 severity and mortality, indicating their potential as genetic biomarkers for risk stratification. These findings support the importance of host genetics in disease progression and may guide future personalized treatment strategies for this condition.