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The Reason More Men Die From COVID-19 May Lie in Their Chromosomes

Women have an inherent genetic advantage when it comes to fighting infectious diseases.

By Nathaniel Scharping
Apr 13, 2020 2:00 PMNov 3, 2020 5:11 PM
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(Credit: Photographee.eu/Shutterstock)


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As the COVID-19 pandemic unfolds, doctors are confronting the stark reality that the virus doesn’t seem to kill equally. From the data available so far, we’ve learned that men are at a far higher risk of dying from the novel coronavirus, SARS-CoV-2, than are women.

In both Michigan and Washington state, for example, data on reported cases show more women than men have contracted the coronavirus. But men make up more than half of the deaths in both states. In New York, men have both contracted and died from the coronavirus at higher rates.

The differences in mortality are often put down to men behaving more riskily. But there’s another explanation for women’s immunological advantage. According to Sharon Moalem, a physician and author, women have an inherent advantage when it comes to diseases because of their two X chromosomes.

Men have an XY chromosome pairing, and it means they miss out on extra copies of some genes that could make a difference when it comes to fighting infectious diseases like that caused by the coronavirus. Hormones play a role as well: Testosterone can inhibit the immune system, while estrogen can stimulate it.

Moalem explores the topic in his book The Better Half: On the Genetic Superiority of Women. He talked with Discover recently about why women have a genetic advantage, and what that means during a pandemic like COVID-19.

Q: What advantages do women get from their two X chromosomes?

A: Having two X chromosomes was not appreciated for many years. It was always thought women simply had a backup; a spare tire. If they lacked a specific gene for color vision on the X chromosome, it was OK because they always had another X chromosome they could draw on.

But it’s not just that women have this extra X chromosome and it’s a redundancy they can swap in as they need. Females really are made of two populations of cells. Every organ and every system around the body is predominantly using one X chromosome over the other.

Many of the genes on the X chromosome have to do with making and maintaining the brain and making and maintaining the immune system. So having two populations of cells — where one is predominantly using one X chromosome over the other — that can interact and cooperate is an immense advantage when you’re faced with unforeseen challenges in life, such as famine and pandemics.

And there are other genes on the X chromosome that are also involved in the immune system to allow it to be better at killing viruses. Two populations of cells working together is an immense advantage when I can only marshal up the same identical X chromosome in all of my cells.

Q: What are the implications of women’s genetic superiority for the current coronavirus pandemic?

A: A simplified way of thinking about that is this: A specific gene on the X chromosome, TLR-7, is often used to recognize single-stranded RNA viruses like the novel coronavirus. Having two versions gives them an advantage in recognizing the virus.

Additionally, we think that COVID-19 uses its spike protein to enter cells in the body. They do that by unlocking the ACE2 protein on the surface of the cell. And, as it turns out, the ACE2 gene is on the X chromosome. Which means all of men’s cells are using that same [version of the] ACE2 gene. So if they unfortunately encounter a strain of COVID-19 that has a spike protein that can perfectly unlock their ACE2 and enter their cells, men are in big trouble quickly.

On the other hand, in females’ cells, 50 percent are going to be using likely a slightly different version of the ACE2 than other cells. It’s much more difficult for a strain of corona to have a spike protein that could equally infect both populations of cells.

Q: Are there any disadvantages to having two X chromosomes?

A: The one cost women need to bear, and it is a serious one, is a much higher risk for autoimmune diseases. For lupus, for example, it’s seven to nine women for every man that is affected.

Their immune system is so much more aggressive and is made up of two populations of cells, so that predisposes women to have their immune cells turn against the body.

Q: Don’t some of the differences in COVID-19 mortality rates for men simply come down to behavior?

A: What I found to be intellectually lazy was a rush to blame the increased male mortality rate on behavior. Of course, proper hand washing has big implications for disease acquisition prevention, but to say that’s why more men are ending up in the ICU and dying didn’t really cut it for me. But that’s the first thing people rushed to for an explanation.

And then we heard about smoking, tobacco use, alcohol and other factors. Which play an immense role in disease outcomes, don’t get me wrong. But what I’m talking about is so fundamental, starts so early in life and is the same throughout the life course.

Q: Given that women might have an immunological genetic advantage, how should this change the way we fight the coronavirus?

A: The realization is that we should be taking care of our male elders because they’re so much more fragile. If we were just blaming people for behavior, that’s not going to make a big difference when it comes to health outcomes if in fact it just comes down to the fact that males are more fragile. So we really need to be putting efforts into either quarantining them for longer or making sure they’re not with younger family members that might be infecting them.

It would be great for us to tease out the ways in which females have immunological superiority and see can we then apply that and get male immune cells to behave in the same way.

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