It was noticeable from the initial outbreak in Wuhan that Covid-19 was killing more men than women. By February, data from China, which involved 44,672 confirmed cases of the respiratory disease, revealed the death rate for men was 2.8%, compared to 1.7% among women. For past respiratory epidemics, including Sars, Mers and the 1918 Spanish flu, men were also at significantly greater risk. But why?

Much of the reason for the Covid-19 disparity was put down to mens riskier behaviours around half of Chinese men are smokers, compared with just 3% of women, for instance. But as the coronavirus has spread globally, its proved deadlier to men everywhere that data exists (the UK and US notably and questionably do not collect sex-disaggregated data). Italy, for instance, has had a case fatality rate of 10.6% for men, versus 6% for women, whereas the sex disparity for smoking (now a known risk factor) is smaller there than China 28% of men and 19% of women smoke. In Spain, twice as many men as women have died. Smoking, then, is unlikely to account for all of the sex disparity in Covid-19 deaths.

Age and co-morbidity (pre-existing health conditions, including diabetes, cardiovascular disease or cancer) are the biggest risk factors, and that describes more older men than women. There may also be a sex difference in how people fight infection, due to immunological or hormonal differences oestrogen is shown to increase the antiviral response of immune cells.

If women are mounting a more effective immune response to Covid-19, it could be because many of the genes that regulate the immune system are encoded on the X chromosome. Everybody gets one X chromosome at conception from their mother. However, sex is determined (for the vast majority) by the chromosome received from their father: females get an additional X, whereas males do not (they receive a Y). According to The Better Half by American physician Sharon Moalem, having this second X chromosome gives women an immunological advantage. Every cell in a womans body has twice the number of X chromosomes as a mans, and so twice the number of genes that can be called upon to regulate her immune response, he says. Only one of the X chromosomes in each cell will be active at any time, but having that diversity of options gives women a better immunological toolbox to fight infections.

Moalem describes the possession of XX chromosomes as female genetic superiority. In the case of Covid-19, for instance, the virus uses its spike protein as a key to unlock a receptor protein on the outside of our human cells, called ACE-2, and gain entry. As the ACE-2 protein is on the X chromosome, men will have identical versions of ACE-2 on all their cells if the virus can unlock one, it can unlock all, he wrote recently in a Twitter thread. Women, though, have two different ACE-2 genes on their two X chromosomes, which may make it harder for the Covid-19 virus to break into all their cells, as it has to unlock two different proteins. Furthermore, once the ACE-2 is unlocked, it cannot perform its function, which, in the case of lung cells, is to clear fluid buildup during infection. So males, with all of their ACE-2 proteins affected, will suffer this more than females, he says. Moalem believes this may be the crucial advantage that XX-carrying women have over XY-carrying men in Covid-19 infection mortality.

Its an intriguing theory, and in his provocative book (written before the Covid-19 outbreak) Moalem expands the XX advantage to explain a whole range of life factors, from womens increased longevity to their lesser incidence of autism. It is incontrovertible that women are far less likely to suffer from X-linked genetic disorders, which include everything from Hunter syndrome to colour-blindness, because they usually have an unaffected X chromosome to fall back on. Indeed, in the case of colour vision, Moalem posits that having a second X chromosome can give some women a visual superpower, enabling them to see 100 times the usual colour range due to the extra diversity of receptors they carry on their multiple Xs.

It is striking that Moalem barely references environmental and social factors in a book about sex differences in health outcomes

However, the evidence for other of Moalems claims for the protective role of a second X chromosome, such as in autism spectrum disorders or behavioural traits, is less convincing. A broad range of genes play complex roles in the workings of the brain, and attributing a simple chromosomal relationship is brave. (It should be noted that Moalem authored the questionable The DNA Restart: Unlock Your Personal Genetic Code to Eat for Your Genes, Lose Weight, and Reverse Ageing in 2016.)

Outside of inherited genetic disorders, such as haemophilia, most conditions are attributable to a range of factors, including cultural norms, behaviours and social and environmental aspects as well as a host of biological factors. For Covid-19, for instance, gender-based norms around smoking and hand-washing, collective or individualistic mindsets that affect compliance with social-distance requests, how polluted your city is, whether you are a caregiver, and poverty and nutrition level all play a part in determining your infection risk and disease outcome. And, as weve seen, a range of co-morbidities increase risk are they too made more likely by absence of a second X chromosome? In many cases, such as cancers and lung disease, Moalem believes so a fascinating theory that surely deserves more study.

It is striking, though, that Moalem barely references environmental and social factors in a book about sex differences in health outcomes. This is particularly problematic when discussing sex differences in the brain, given the history of prejudicial research in this area. Much as this reviewer enjoys the rare pleasure of being described as the stronger, better, and superior sex certainly it is a change from being described as the weaker sex, as women have throughout history it is nevertheless an uncomfortable valuation. Claims for significant innate cognitive or behavioural advantages between the sexes have largely been debunked in the past few years by a range of influential books and research, and while there are differences, in most cases these are at least as great between individuals of each sex as between the sexes.

This is, however, a book that openly champions women, and it is most enjoyable when giving centre stage to female scientists, who have been too often overlooked. Moalems point is that, just as womens discoveries have been ignored, so too has the importance of their second X chromosome. Even today, medical and pharmaceutical research overwhelmingly favours male subjects, blinding us to knowledge that could lead to breakthroughs, and disadvantaging women who suffer inappropriate treatments and dosing. As men continue to fill the Covid-19 morgues faster than women, Moalem is on a quest to draw the worlds attention to a chromosomal tool we might just need.

Originally posted here:
The Better Half: On the Genetic Superiority of Women review bold study of chromosomal advantage - The Guardian

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