Association of ACE I/D and TNF‐α‐308 Polymorphisms with COVID‐19 Severity in a Mexican Population

Background: COVID-19 severity shows marked interindividual variability, suggesting a role for host genetic factors. Polymorphisms in genes involved in the renin–angiotensin system and inflammatory response, such as the angiotensin-converting enzyme (ACE) and the tumor nrecorsis factor-alpha (TNF-α), have been proposed as potential modulators of disease severity. Objectives: To evaluate the association between the ACE I/D (rs4646994) and TNF-α −308 G/A (rs1800629) polymorphisms and COVID-19 severity in a Mexican population. Methods: A total of 236 individuals with RT-PCR–confirmed SARS-CoV-2 infection were included. Patients were classified as hospitalized (severe, n = 155) or non-hospitalized (asymptomatic–mild, n = 81). Genotyping was performed by PCR–RFLP. Genotype distributions were analyzed using χ² tests under dominant and recessive genetic models, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: The ACE I/D polymorphism showed a significant association with COVID-19 severity. Carriers of the I allele (ID + II) had a higher risk of hospitalization compared with DD homozygotes (OR = 2.78, 95% CI: 1.53–5.06, p = 0.001). Sex-stratified analysis revealed that this association was significant only in male patients. No significant association was observed between the TNF-α-308 G/A polymorphism and disease severity. Conclusions: The ACE I/D polymorphism is associated with COVID-19 severity in a Mexican population, with a stronger effect observed in males. These findings underscore the relevance of host genetic background and sex-specific effects in COVID-19 outcomes. Further studies including larger cohorts, healthy controls, and multivariable analyses are required to confirm these associations.