Genetic Variants in NOS2 and CCL2 Modulate Risk of Post-COVID-19 Hyperglycemia via Immune-Metabolic Interactions.

Hyperglycemia has increasingly been recognized among individuals recovering from coronavirus disease 2019 (COVID-19); the host factors contributing to heterogeneous metabolic outcomes remain poorly understood. This cohort study investigated the association between innate immune genetic polymorphisms and hyperglycemia in post-COVID-19 patients. A total of 471 adults with previous mild-to-moderate COVID-19 were enrolled through the post-COVID follow-up program at Siriraj Hospital, Thailand, and classified as normoglycemic (HbA1c < 5.7%, n = 252) or hyperglycemic (HbA1c ≥ 5.7%, n = 219). Clinical characteristics, metabolic parameters, inflammatory biomarkers, and immunological measurements were collected during follow-up. Genotyping was performed using the Axiom Human Genotyping SARS-CoV-2 Research Array, focusing on candidate polymorphisms in innate immune-related genes. Associations between genetic variants and hyperglycemia were evaluated using multivariable logistic regression adjusted for age, body mass index, and underlying comorbidities. Participants with hyperglycemia were significantly older and had higher body mass index, greater prevalence of cardiometabolic comorbidities, elevated C-reactive protein levels, and higher LDL cholesterol compared with normoglycemic individuals. Significant associations were identified in NOS2 and CCL2. The NOS2 rs4795067 variant was associated with increased odds of hyperglycemia (adjusted OR = 1.770, 95% CI: 1.137-2.756, p = 0.011), whereas rs35051118 showed a protective effect (adjusted OR = 0.613, 95% CI: 0.386-0.975, p = 0.039). In CCL2, rs28730833 was strongly associated with hyperglycemia (adjusted OR = 2.977, 95% CI: 1.349-6.572, p = 0.007). These findings suggest that innate immune genetic variation may contribute to hyperglycemia in post-COVID-19 patients, although independent validation is required.