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The role of X and Y chromosomes in asthma

The role of X and Y chromosomes in asthma

Monday, April 24, 2023

Researchers from the Woolcock Institute of Medical Research have found that sex cannot only influence the likelihood of who will suffer from asthma, but also how severe their symptoms will be. 

Sex differences are prevalent across almost all organ systems and diseases, but particularly so when it comes to asthma, a chronic inflammatory disease of the lungs that affects almost 11 percent of the Australian population.

PhD student Diren Reddy has always been interested in finding out how biological sex influences the way medical conditions present and evolve. So when he found out that more male children suffer from asthma than female children - a trend that is reversed when puberty hits - he was keen to investigate why.  

“Pre-pubescent male children have a higher incidence and hospitalisation rate of asthma compared to females. After puberty, however, you see a switch, with females having increased rates of asthma with worse severity,” Reddy says.

“When I saw this in my research, I realised that there is a complex interaction between sex and disease that needed further investigating.” 

We all have a set of chromosomes that carry our genes, and some of these chromosomes determine our sex - they're called the sex chromosomes. Males have one X and one Y chromosome, while females have two X chromosomes.

Some genes are located on the sex chromosomes, and the way they're expressed (turned on or off) can differ between males and females. This is because males have only one copy of the gene, while females have two copies. Broadly speaking, the expression of genes on the sex chromosomes can be influenced by a variety of factors, and differences in the function of these genes can lead to differences between males and females.

Reddy believes that the answers to asthma-related differences between males and females lie in the Y chromosome. Unlike the X chromosome, the Y chromosome is commonly disregarded and considered a genetic wasteland as it is significantly smaller and contains fewer genes. 

“However, I believe that this chromosome is where the imbalance in asthma susceptibility and severity lies between males and females. Females can't produce genes on the Y chromosome because they don't have one, and a growing body of work shows that these genes contribute to critical biological processes,” Reddy says. 

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At first, Reddy looked to the sex hormones - oestrogen and testosterone - to see if they contribute sex differences in important asthma processes. While they appear to affect the severity of asthma, it remains unclear if they are causing increased rates of asthma in either sex. 

Using gene-editing technology to deactivate genes on the Y chromosome, Reddy was able to see that when it comes to the inflammatory response in asthma (which involves the body's immune system reacting to irritants in the airways, such as pollen, dust, or pet dander by releasing chemicals such as histamine and leukotrienes, which cause inflammation) these previously disregarded genes have an important role. 

As females do not produce these genes, males may be protected or be worse off due to the function of these Y-chromosome genes.

“When we removed cells from the airways of males and female patients, we also removed them from the direct influence of the sex hormones, and a difference was still seen,” Reddy says. 

“Importantly, that means something inherently different that exists within male and female cells that causes a different response to asthma between the sexes. And the fact which remains different is the sex chromosomes.” 

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