Understanding COVID-19: A hypothesis regarding digit ratio (2D:4D), ACE I/D polymorphism, oxygen metabolism and national case fatality rates.

ABSTRACT

OBJECTIVE: Male digit ratio (2D4D) correlates positively with the national case fatality rate (CFR) for COVID-19. The severity of COVID-19 may be influenced by a counterbalance between the angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2). SARS-CoV2 cleaves with ACE2 and enters cells leaving an unopposed effect of ACE in the lungs. Both 2D4D and the ACE I/D polymorphism are covariates of oxygen metabolism. COVID-19 leads to lung damage and a reduction in oxygen saturation of the blood. Here, we examine the interrelationships between 2D4D, ACE polymorphism, and COVID-19 CFR. METHODS: National frequencies/rates were obtained for 2D4D from the BBC Internet study (n = 41), published values of ACE I/II (n = 39), and COVID-19 CFR from three World Health Organization situation reports (n = 41). RESULTS: 2D4D was negatively associated with national ACE I/II frequencies. However, there was a positive relationship between male 2D4D and CFR (right and left 2D4D, two, and three situation reports respectively). The relationships between ACE I/II and CFR were non-significant. Relationships between male 2D4D and CFR's were independent of female 2D4D and ACE I/II. CONCLUSIONS: The ACE I/D polymorphism may influence 2D4D such that ACE II individuals have lower 2D4D than ACE DD individuals. Low 2D4D and ACE II individuals show efficient oxygen metabolism. Therefore, low 2D4D and ACE II together may protect against COVID-19 severity. The sex-dependent positive correlation between male 2D4D and CFR is independent of ACE I/II, suggesting that the sex-dependent variation in the ACE2 gene may also influence the 2D4D phenotype.