ACE2 and the variability hypothesis for Covid-19

One of the big mysteries of Covid-19 has been the difference in severity between men and women. About 2/3 of deaths have been among men, despite the fact that there are far more women than men in the most vulnerable age groups. This has been attributed to general differences between men and women in immune responses — women being generally more resistant to infection, and more susceptible to auto-immune diseases.

I recently went to look up the genetics of ACE2 — the membrane protein that SARS-Cov-2 uses to enter human cells — and discovered the basic fact (presumably known to anyone familiar with biochemistry) that the ACE2 gene is on the X chromosome. And that made me think of the infamous “variability hypothesis”. This is the notion that men are generally more variable in many characteristics than women, so will be overrepresented among the extremes at both ends of the distribution. Of course, as with any scientific fact about men and women, this has been primarily used to argue that women should mind their knitting and cannot be comparable to male geniuses like (most notoriously) Larry Summers.

Such essentialist arguments are wrong-headed and demeaning when applied to characteristics as complex as intelligence, much less to something as vaguely defined as “commitment” (Summers’s word). But this phenomenon is well grounded where it is applied to genetic traits linked to the X chromosome. Female bodies are mosaics, with each cell randomly expressing one of the two inherited versions of the X chromosome. It is extremely well known and uncontroversial in the context of X-linked Mendelian disorders, such as haemophilia and red-green colour-blindness. A single defective gene on the X chromosome causes these conditions, where a mixture of defective and healthy alleles produces a phenotype essentially indistinguishable from the healthy version alone.

The general phenomenon is superlinearity of effect: Where an average of two scores produces a markedly different outcome from one or the other extreme. Might that be the case for Covid-19? There is some evidence from Italian populations that variants in the ACE2 gene may affect individual susceptibility to severe Covid-19. Indeed, this study suggests that rare variants may play a significant role. If a mixture of half highly susceptible cells and half less susceptible is much more robust than a tissue where all cells are highly susceptible — a plausible situation, though not inevitable — then we would expect to see more severe disease in males.

Looking around, I found this paper that points out that men have generally higher levels of ACE2 circulating in blood, and argues “due to the high expression of ACE2, male patients may be more likely to develop severe symptoms and die of SARS-CoV-2”. So that’s another possibility.

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