Association of EGLN1 and EGLN3 genetic variants with COVID-19 severity in a Mexican population

Hypoxia-inducible factors, particularly HIF-1α, are key regulators of cellular adaptation to hypoxia and play an important role in inflammatory signaling. In severe COVID-19, cytokine-driven disruption of iron metabolism results in elevated ferritin levels, a marker consistently associated with systemic inflammation and adverse clinical outcomes. We investigated whether genetic variants in Egl nine homolog 1 (EGLN1) (rs516651, rs12406290, rs1769793) and Egl nine homolog 3 (EGLN3) (rs12879626, rs11156819, rs1346902), which encode prolyl hydroxylase domain enzymes that regulate HIF stability, are associated with COVID-19 severity. We conducted a cross-sectional study prior to the national COVID-19 vaccination program, including 627 participants classified according to WHO severity criteria. Serum levels of D-dimer, ferritin, IL-6, and IFN-γ were quantified and compared across severity groups. Associations between genetic variants and disease severity were assessed using multivariate logistic regression models. Ferritin levels increased progressively with COVID-19 severity. The T allele (rs1769793) showed a lower oxygen saturation distribution. In addition, after Bonferroni correction, the rs1769793 CT allele of the codominant model showed an OR = 3.2 (95% CI = 1.42–7.5; P = 0.005), and the CT + TT allele of dominant model had an OR = 3.01 (95% CI = 1.37–6.58; P = 0.006), both were associated with an increased risk of death. Subjects carrying the rs1769793 variant exhibited reduced oxygen saturation levels and were at increased risk of death.