Association of Endothelial Nitric Oxide Synthase Polymorphisms with Clinical Severity in Patients with COVID-19

Background/Objectives: To elucidate the factors that contribute to individual variability in the progression of COVID-19, experiments on endothelial nitric oxide synthase polymorphisms have been reported. Nitric oxide synthase (NOS3) is located in the endothelium and is involved in the regulation of inflammation and vascular homeostasis. In this study, we investigated the association between COVID-19 severity and NOS3 G894T and NOS3 27-bp VNTR 4b/a genetic polymorphisms. Methods: Patients with COVID-19 (n = 178) were divided into Group 1 (mild disease) and Group 2 (severe disease) based on oxygen saturation levels in room air (Group 1, SpO₂ ≥ 93%, n = 107; and Group 2, SpO₂ < 93%, n = 73) and hospitalization requirements. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. Results: Overall, genotype and allele frequencies of the NOS3 genetic polymorphisms were similar across the two study groups (p > 0.05). However, the subgroup analysis showed a notable trend for the 4b/4a allele distribution between Groups 1 and 2. In the younger subgroup of patients (≤50 years old) without chronic obstructive pulmonary disease, Group 2 tended to have a higher frequency of the 4b allele than Group 1 (97.4% vs. 85.4% p = 0.06) and a higher occurrence of 4b/4b genotype (94.7% vs. 74.0%, p = 0.05). Additionally, a rarely observed 4c allele was detected only in two subjects within Group 2 but not in Group 1. Conclusions: These findings suggest a trend of association between COVID-19 severity and NOS3 27-bp VNTR 4b/a genetic polymorphism. Genetic analysis may reveal patient susceptibility to disease, prognosis risk factors, and drug responsiveness.