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 (2D:4D) 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 2D:4D 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 2D:4D, ACE polymorphism, and COVID-19 CFR. Methods National frequencies/rates were obtained for 2D:4D 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 2D:4D was negatively associated with national ACE I/II frequencies. However, there was a positive relationship between male 2D:4D and CFR (right and left 2D:4D, two, and three situation reports respectively). The relationships between ACE I/II and CFR were non-significant. Relationships between male 2D:4D and CFR's were independent of female 2D:4D and ACE I/II. Conclusions The ACE I/D polymorphism may influence 2D:4D such that ACE II individuals have lower 2D:4D than ACE DD individuals. Low 2D:4D and ACE II individuals show efficient oxygen metabolism. Therefore, low 2D:4D and ACE II together may protect against COVID-19 severity. The sex-dependent positive correlation between male 2D:4D and CFR is independent of ACE I/II, suggesting that the sex-dependent variation in the ACE2 gene may also influence the 2D:4D phenotype.

No credible evidence for links between 2D:4D and COVID-19 outcomes: A probabilistic perspective on digit ratio, ACE variants, and national case fatalities

“…In short, according to the model of Manning and Fink (1), even a very small change in digit ratio should produce an implausibly large increase in mortality, which questions the credibility of their reported results. That these relationships hold over time unfortunately does not aid in their interpretation (2,3).…”

“…In a recent series of articles, Manning and Fink report the association of national-level index to ring finger ratio (2D:4D) with national case fatality rates (1)(2)(3), and test the associations of national-level ACE1 allele frequency and the ACE2 genotype on the same outcome (3). 2D:4D has long been thought to correlate negatively with prenatal androgen exposure, such that shorter index fingers relative to ring fingers indicate more prenatal androgen exposure (12).…”

“…2D:4D has long been thought to correlate negatively with prenatal androgen exposure, such that shorter index fingers relative to ring fingers indicate more prenatal androgen exposure (12). However, interestingly Manning and Fink report that countries with higher male 2D:4D ratios actually have higher case fatality ratios, suggesting that higher levels of prenatal testosterone may confer protection from COVID-19 symptoms (2,3). Manning and Fink suggest that this may be due to the frequency of the ACE2 genotype within a nation, higher levels of which reduce COVID-19 severity, while also demonstrating negative correlations between national level ACE1 allele frequency and ACE2 genotype frequency and national level 2D:4D (3), which are both thought to relate to androgen exposure (6,12).…”

Understanding the Geography of COVID-19 Case Fatality Rates in China: A Spatial Autoregressive Probit-Log Linear Hurdle Analysis

“…However, the related data of each city is not available in China, so we cannot consider the effects of them in the model. Finally, the biological differences of residents among different cities can be taken into consideration in the future studies on determinants on the CFR with COVID-19 at the city level, including the effects of digit ratio (2D:4D) and ACE (Angiotensin-Converting Enzyme) I/D polymorphism on the CFR (55)(56)(57)(58).…”

COVID-19 and syndemic challenges in ‘Battling the Big Three’: HIV, TB and malaria

“…A genetic deletion/insertion of a 285 bp Alu repeat sequence in intron 16 of the ACE gene fragment insertion (I allele) or its absence (D allele) is of particular importance. Insertion of the extra fragment (ACE I allele) is associated with lower ACE activity, whereas its absence (ACE D allele) leads to higher ACE activity (Woods et al, 2000;Manning and Fink, 2020) and angiotensin II levels (Sarangarajan et al, 2020). While the ACE I/D genotype modulates ACE2 expression and the ACE D allele is associated with the infection course and mortality due to COVID-19 (Delanghe et al, 2020;Yamamoto et al, 2020), an earlier study has shown that the ACE I/D and ACE D/D genotypes provide relative protection from cerebral malaria in an Indian cohort (Dhangadamajhi et al, 2010).…”